JP2010540517A - HIV protease inhibitor - Google Patents

Abstract

、
ここで、Ｘ^Ａ、ｋ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^５Ａ、Ｒ^６、Ｒ^６Ａ、Ｒ^７およびＲ^８は、本書に定義されている。式Ｉに包含される化合物には、ＨＩＶプロテアーゼ阻害剤である化合物、および生体内で代謝されてＨＩＶプロテアーゼ阻害剤となりうるその他の化合物が含まれる。化合物および医薬品として容認できるそれらの塩は、ＨＩＶ感染の予防または治療およびエイズの予防、治療、またはその発症の遅延に有用である。化合物およびそれらの塩は、薬剤組成物の成分として採用でき、他の抗ウイルス薬、免疫調節薬、抗生物質またはワクチンと任意的に組み合わせることができる。A compound of formula I is disclosed.

,
Here, X ^A , k, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5A , R ⁶ , R ^6A , R ⁷ and R ⁸ are defined in this document. Compounds encompassed by Formula I include compounds that are HIV protease inhibitors, and other compounds that can be metabolized in vivo to become HIV protease inhibitors. The compounds and their pharmaceutically acceptable salts are useful for the prevention or treatment of HIV infection and the prevention, treatment or delay of onset of AIDS. The compounds and their salts can be employed as components of pharmaceutical compositions and can optionally be combined with other antiviral agents, immunomodulators, antibiotics or vaccines.

Description

  The present invention relates to certain lysinesulfonamide derivatives and their pharmaceutically acceptable salts. These derivatives include compounds that are HIV protease inhibitors, and others that can be metabolized in vivo to become HIV protease inhibitors. The compounds are useful for preventing HIV infection and HIV replication, treating HIV infection and HIV replication, preventing AIDS, treating AIDS, and delaying the onset and / or progression of AIDS.

Retroviruses called human immunodeficiency virus (HIV), in particular the strains known as HIV type 1 (HIV-1) and type 2 (HIV-2) viruses, have been found in the immune system, destruction of CD4 T-cells, Acquired immune deficiency syndrome (AIDS), a disease characterized by susceptibility to infection, and its precursor, a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss It is a pathogen of an AIDS related syndrome (“ARC”). This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retroviral replication is the extensive post-translational processing of precursor polyproteins by virally encoded proteases to produce the mature viral proteins necessary for viral assembly and function. Inhibiting this treatment usually prevents the generation of infectious viruses. For example, in “Kohl et al., Proc. Nat'l Acad. Sci. 1988, 85 : 4686”, genetic inactivation of HIV-encoded protease results in immature and non-infectious It has been demonstrated that virus particles are produced. These results indicate that inhibition of HIV protease is a viable method for treating AIDS and preventing or treating HIV infection.

Nucleotide sequencing of HIV indicates the presence of the pol gene within one ORF (Open Reading Frame) [Ratner et al. , Nature 1985, 313 : 277]. The amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, endonuclease, HIV protease and gag, which encodes the core protein of the viral particle [Toh et al . , EMBO J. et al. 1985, 4 : 1267, Power et al. , Science 1986, 231 : 1567, Pearl et al. , Nature 1987, 329 : 351].

At present, several HIV protease inhibitors have been approved for clinical use in the treatment of AIDS and HIV infection, including indinavir (see US54139999), amprenavir (US558597), saquinavir (US5196438), Ritonavir (US 5484801) and nelfinavir (US 5484926) are included. Each of these protease inhibitors are competitive inhibitors of peptide-derived peptidomimetic viral proteases that prevent cleavage of the HIV gag-pol polyprotein precursor. Tipranavir (US5852195) is a non-peptide peptidomimetic protease inhibitor that is also approved for the treatment of HIV infection. Protease inhibitors include at least one and generally at least two other HIV antiviral drugs, in particular nucleoside reverse transcriptase inhibitors such as zidovudine (AZT) and lamivudine (3TC) and / or efavirenz and nevirapine Of non-nucleoside reverse transcriptase inhibitors. For example, indinavir has been shown to be very effective in reducing HIV viral load and increasing CD4 cell count in HIV-infected patients when used in combination with nucleoside reverse transcriptase inhibitors. See, for example, “Hammer et al., New England J. Med. 1997, 337 : 725-733” and “Gulick et al., New England J. Med. 1997, 337 : 734-739”.

  Treatments established using protease inhibitors are not suitable for use on all HIV-infected subjects. For example, some subjects cannot tolerate these treatments due to side effects. Many subjects infected with HIV often develop resistance to specific protease inhibitors. Accordingly, there continues to be a need for new compounds that are capable of inhibiting HIV protease and that are suitable for use in treating or preventing HIV infection and / or treating or preventing AIDS or delaying its onset or progression.

  References disclosing amino acid derivatives having the property of inhibiting HIV aspartyl protease, processes for the preparation of the derivatives, and / or therapeutic uses of the derivatives include WO 01/68593, WO 02/064551 A1, WO 03/074467 A2, WO2004 / 056764 A1, WO2006 / 012725 A1, WO2006 / 114001 A1, WO2007 / 062526 A1, WO2008 / 023273 A2, WO2008 / 078200 A2, and US7388008 B2.

US Pat. No. 5,413,999 US Pat. No. 5,585,397 US Pat. No. 5,196,438 US Pat. No. 5,484,801 US Pat. No. 5,484,926 US Pat. No. 5,852,195 International Publication No. 01/68593 International Publication No. 02/064551 International Publication No. 03/074467 International Publication No. 2004/056764 International Publication No. 2006/012725 International Publication No. 2006/114001 International Publication No. 2007/062526 International Publication No. 2008/023273 International Publication No. 2008/078200 US Pat. No. 7,388,008

Kohl et al. , Proc. Nat'l Acad. Sci. 1988, 85: 4686 Ratner et al. , Nature 1985, 313: 277. Toh et al. , EMBO J. et al. 1985, 4: 1267 Power et al. , Science 1986, 2311: 1567 Pearl et al. , Nature 1987, 329: 351. Hammer et al. , New England J .; Med. 1997, 337: 725-733. Gulick et al. , New England J .; Med. 1997, 337: 734-739

(Summary of the Invention)
The present invention relates to certain lysinesulfonamide derivatives and their use, inhibition of HIV protease, prevention of HIV infection, treatment of HIV infection, and prevention, treatment of AIDS, and delay of its onset or progression. More particularly, the present invention includes compounds of formula I

、
および医薬品として容認できるそれらの塩が含まれ、ここで：
Ｒ^１は、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルであり、
Ｒ^２は、ＣＨ（Ｒ^Ｊ）−Ｚであり、Ｚは、ＯＨ、ＮＨ_２、またはＯＲ^Ｐであり、
Ｒ^Ｊは、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−５シクロアルキルで置換したＣ_１−６アルキルであり、
Ｒ^Ｐは、Ｐ（Ｏ）（ＯＨ）_２、Ｐ（Ｏ）（ＯＭ）_２、またはＣ（Ｏ）Ｒ^Ｑであり、
Ｍは、アルカリ金属またはアルカリ土類金属であり、
Ｒ^Ｑは：
（１）Ｃ_１−６アルキル、
（２）Ｃ_３−６シクロアルキル、
（３）Ｃ_３−６シクロアルキルで置換したＣ_１−６アルキル、
（４）Ｏ−Ｃ_１−６アルキル、
（５）Ｏ−Ｃ_１−６アルキルで置換したＯ−Ｃ_１−６アルキル、
（６）Ｏ−Ｃ_１−６フルオロアルキル、
（７）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキル、
（８）Ｃ（Ｏ）−Ｃ_１−６アルキレン−Ｎ（Ｈ）−Ｃ_１−６アルキル、
（９）Ｃ（Ｏ）−Ｃ_１−６アルキレン−Ｎ（−Ｃ_１−６アルキル）_２、
（１０）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキルで置換したＣ_１−６アルキル、
（１１）Ｃ（Ｏ）ＯＨで置換したＣ_１−６アルキル、
（１２）Ｃ（Ｏ）−Ｃ_１−６アルキルで置換したＣ_１−６アルキル、
（１３）Ｎ（Ｈ）−Ｃ_１−６アルキル、
（１４）Ｎ（−Ｃ_１−６アルキル）_２、
（１５）ＮＨ_２、Ｎ（Ｈ）−Ｃ_１−６アルキル、またはＮ（−Ｃ_１−６アルキル）_２で置換したＣ_１−６アルキル、
（１６）ＡｒｙＡ、
（１７）ＡｒｙＡで置換したＣ_１−６アルキル、
（１８）ＡｒｙＡで置換したＯ−Ｃ_１−６アルキル、
（１９）ＨｅｔＡ、
（２０）ＨｅｔＡで置換したＣ_１−６アルキル、
（２１）ＨｅｔＡで置換したＯ−Ｃ_１−６アルキル、
（２２）ＨｅｔＢ、または
（２３）Ｏ−ＨｅｔＢ、
であり、
Ｒ^３は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルであり、
Ｒ^４は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルであり、
Ｒ^５は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、ＯＨで置換したＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルであり、
Ｒ^５Ａは、ＨまたはＣ_１−６アルキルであり、
あるいは、Ｒ^５およびＲ^５Ａは、両方が結合する炭素原子とともにＣ_３−６シクロアルキルを形成し、
ただし：
（Ａ）Ｒ^２がＣＨ_２ＯＨまたはＣＨ_２ＯＲ^Ｐのときには、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^５Ａのうち少なくとも１つはＨではなく、
（Ｂ）Ｒ^５およびＲ^５Ａのどちらかまたは両方がＨではないときには、Ｒ^３およびＲ^４のうち少なくとも１つはＨであり、および
（Ｃ）Ｒ^３およびＲ^４がどちらもＨでないときには、Ｒ^５およびＲ^５ＡはどちらもＨであり、
それぞれのＸ^Ａは、独立的に：
（１）Ｃ_１−６アルキル、
（２）Ｃ_３−６シクロアルキル、
（３）Ｃ_１−６ハロアルキル、
（４）ＯＨ
（５）Ｏ−Ｃ_１−６アルキル、
（６）Ｏ−Ｃ_１−６ハロアルキル、
（７）Ｏ−Ｃ_３−６シクロアルキル、
（８）ＳＨ、
（９）Ｓ−Ｃ_１−６アルキル、
（１０）Ｓ−Ｃ_１−６ハロアルキル、
（１１）Ｓ−Ｃ_３−６シクロアルキル、
（１２）ハロ、
（１３）ＣＮ、
（１４）ＮＯ_２、
（１５）ＮＨ_２、
（１６）Ｎ（Ｈ）−Ｃ_１−６アルキル、
（１７）Ｎ（−Ｃ_１−６アルキル）_２、
（１８）Ｎ（Ｈ）Ｃ（Ｏ）−Ｃ_１−６アルキル、
（１９）Ｎ（Ｈ）ＣＨ（Ｏ）、
（２０）ＣＨ（Ｏ）、
（２１）Ｃ（Ｏ）−Ｃ_１−６アルキル、
（２２）Ｃ（Ｏ）ＯＨ、
（２３）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキル、
（２４）ＳＯ_２Ｈ、
（２５）ＳＯ_２−Ｃ_１−６アルキル、または
（２６）
（ａ）Ｃ_３−６シクロアルキル、
（ｂ）Ｃ_１−６ハロアルキル、
（ｃ）ＯＨ、
（ｄ）Ｏ−Ｃ_１−６アルキル、
（ｅ）Ｏ−Ｃ_１−６ハロアルキル、
（ｆ）Ｏ−Ｃ_３−６シクロアルキル、
（ｇ）ＳＨ、
（ｈ）Ｓ−Ｃ_１−６アルキル、
（ｉ）Ｓ−Ｃ_１−６ハロアルキル、
（ｊ）Ｓ−Ｃ_３−６シクロアルキル、
（ｋ）ハロ、
（ｌ）ＣＮ、
（ｍ）ＮＯ_２、
（ｎ）ＮＨ_２、
（ｏ）Ｎ（Ｈ）−Ｃ_１−６アルキル、
（ｐ）Ｎ（−Ｃ_１−６アルキル）_２、
（ｑ）Ｎ（Ｈ）Ｃ（Ｏ）−Ｃ_１−６アルキル、
（ｒ）Ｎ（Ｈ）ＣＨ（Ｏ）、
（ｓ）ＣＨ（Ｏ）、
（ｔ）Ｃ（Ｏ）−Ｃ_１−６アルキル、
（ｕ）Ｃ（Ｏ）ＯＨ、
（ｖ）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキル、
（ｗ）ＳＯ_２Ｈ、または
（ｘ）ＳＯ_２−Ｃ_１−６アルキル、
で置換したＣ_１−６アルキル
であり、
あるいは、２つ以上のＸ^Ａ置換基がフェニル環に存在し、およびＸ^Ａのうち２つがフェニル環の隣接した炭素原子に結合しているときには、その２つのＸ^Ａは、それらが結合している炭素原子とともに、フェニル環に融合された５員または６員の飽和または不飽和の複素環を形成してもよく、ここでこの複素環には、Ｎ、ＯおよびＳから独立的に選択される１から２個のヘテロ原子が含まれ、
Ｋは、０、１、２、または３に等しい整数であり、
Ｒ^６は：

,
And their pharmaceutically acceptable salts include, where:
R ¹ _{is C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 C 1-6} alkyl substituted with cycloalkyl or _{C 3-6} cycloalkyl,
R ² is CH (R ^J ) —Z, Z is OH, NH ₂ , or OR ^P ;
R ^J is, _H, a _{C 1-6 alkyl, C 1-6} fluoroalkyl or _{C 1-6} alkyl substituted with _{C 3-5} cycloalkyl,
R ^P is P (O) (OH) ₂ , P (O) (OM) ₂ , or C (O) R ^Q ;
M is an alkali metal or alkaline earth metal;
^RQ is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C (O) —C _1-6 alkylene-N (H) —C _1-6 alkyl,
(9) C (O) —C _1-6 alkylene-N (—C _1-6 alkyl) ₂ ,
(10) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(11) C _1-6 alkyl substituted with C (O) OH;
(12) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(13) N (H) —C _1-6 alkyl,
(14) N (—C _1-6 alkyl) ₂ ,
(15) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(16) AryA,
(17) C _1-6 alkyl substituted with AryA,
(18) O—C _1-6 alkyl substituted with AryA,
(19) HetA,
(20) C _1-6 alkyl substituted with HetA,
(21) O—C _1-6 alkyl substituted with HetA,
(22) HetB, or (23) O-HetB,
And
R ³ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl,
R ⁴ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl,
R ⁵ is, _{H, C 1-6 alkyl, C 1-6} fluoroalkyl alkyl, _C substituted with OH _{1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6} cycloalkyl or C, C _1-6 alkyl substituted with _3-6 cycloalkyl,
R ^5A is H or C _1-6 alkyl;
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-6 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) When either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H; and (C) When R ³ and R ⁴ are not H, R ⁵ and R ^5A are both H;
Each of ^{X A} is, independently:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 haloalkyl,
(4) OH
(5) O—C _1-6 alkyl,
(6) O—C _1-6 haloalkyl,
(7) O—C _3-6 cycloalkyl,
(8) SH,
(9) S—C _1-6 alkyl,
(10) S—C _1-6 haloalkyl,
(11) S—C _3-6 cycloalkyl,
(12) Halo,
(13) CN,
(14) NO ₂ ,
(15) NH ₂ ,
(16) N (H) -C _1-6 alkyl,
(17) N (—C _1-6 alkyl) ₂ ,
(18) N (H) C (O) —C _1-6 alkyl,
(19) N (H) CH (O),
(20) CH (O),
(21) C (O) —C _1-6 alkyl,
(22) C (O) OH,
(23) C (O) O—C _1-6 alkyl,
(24) SO ₂ H,
₍₂₅₎ SO _{2 -C 1-6} alkyl or,
(26)
(A) C _3-6 cycloalkyl,
(B) C _1-6 haloalkyl,
(C) OH,
(D) O—C _1-6 alkyl,
(E) O—C _1-6 haloalkyl,
(F) O—C _3-6 cycloalkyl,
(G) SH,
(H) S—C _1-6 alkyl,
(I) S—C _1-6 haloalkyl,
(J) S—C _3-6 cycloalkyl,
(K) Halo,
(L) CN,
(M) NO ₂ ,
(N) NH ₂ ,
(O) N (H) -C _1-6 alkyl,
(P) N (—C _1-6 alkyl) ₂ ,
(Q) N (H) C (O) —C _1-6 alkyl,
(R) N (H) CH (O),
(S) CH (O),
(T) C (O) —C _1-6 alkyl,
(U) C (O) OH,
(V) C (O) O—C _1-6 alkyl,
(W) _SO 2 H, or _(x) SO _{2 -C 1-6} alkyl,
C _1-6 alkyl substituted with
Alternatively, two or more X ^A substituent is present on the phenyl ring, and when it two of X ^A is attached to the carbon atom adjacent to the phenyl ring, its two X ^A, and they are attached Together with a carbon atom may form a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains 1 to 2 heteroatoms,
K is an integer equal to 0, 1, 2, or 3;
R ⁶ is:

であり、ここで星印（＊）は、化合物の他の部分への結合点を示し、
Ｒ^６Ａは、ＨまたはＣ_１−６アルキルであり、
あるいは、Ｒ^６およびＲ^６Ａは、これらが結合している炭素とともにＣ_３−６シクロアルキル（フェニルで任意に置換され、ここで、フェニルは１から３個のＸ^Ｂで任意に置換される。）を形成し、
それぞれのＸ^ＢおよびそれぞれのＸ^Ｃは、

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
R ^6A is H or C _1-6 alkyl;
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached are optionally substituted with C _3-6 cycloalkyl (wherein phenyl is optionally substituted with 1 to 3 X ^B. )
Each X ^B and each X ^C is

(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 haloalkyl,
(4) OH,
(5) O—C _1-6 alkyl,
(6) O—C _1-6 haloalkyl,
(7) O—C _3-6 cycloalkyl,
(8) SH,
(9) S—C _1-6 alkyl,
(10) S—C _1-6 haloalkyl,
(11) S—C _3-6 cycloalkyl,
(12) Halo,
(13) CN,
(14) NO ₂ ,
(15) NH ₂ ,
(16) N (H) -C _1-6 alkyl,
(17) N (—C _1-6 alkyl) ₂ ,
(18) N (H) C (O) —C _1-6 alkyl,
(19) N (H) CH (O),
(20) CH (O),
(21) C (O) —C _1-6 alkyl,
(22) C (O) OH,
(23) C (O) O—C _1-6 alkyl,
(24) SO ₂ H,
₍₂₅₎ SO _{2 -C 1-6} alkyl, and (26)
(A) C _1-6 haloalkyl,
(B) OH
(C) O—C _1-6 alkyl,
(D) O—C _1-6 haloalkyl,
(E) O—C _3-6 cycloalkyl,
(F) SH,
(G) S—C _1-6 alkyl,
(H) Halo,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) —C _1-6 alkyl,
(M) N (—C _1-6 alkyl) ₂ ,
(N) C (O) —C _1-6 alkyl,
(O) C (O) OH,
(P) C (O) O—C _1-6 alkyl, or (q) SO ₂ —C _1-6 alkyl,
Independently selected from the group consisting of C _1-6 alkyl substituted with
T is O, S, S (O), or SO ₂ ;
m is an integer equal to 0, 1, 2, or 3;
n is an integer equal to 0, 1, 2, or 3;
R ⁷ is, _H, a _{C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6} alkyl substituted with _{C 3-6} cycloalkyl or C (O) -R ^K,,
R ⁸ is H or C _1-6 alkyl;
^RK is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(9) C _1-6 alkyl substituted with C (O) OH,
(10) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(11) N (H) -C _1-6 alkyl,
(12) N (—C _1-6 alkyl) ₂ ,
(13) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(14) AryA,
(15) C _1-6 alkyl substituted with AryA,
(16) O—C _1-6 alkyl substituted with AryA,
(17) HetA,
(18) C _1-6 alkyl substituted with HetA,
(19) O—C _1-6 alkyl substituted with HetA,
(20) HetB,
(21) O-HetB, or (22) O-C _1-6 alkyl substituted with HetB,
And
Each AryA is aryl which is independently phenyl or naphthyl, wherein phenyl or naphthyl is substituted from one to any of four Y ^B, each of Y ^B independently identical to X ^B With the definition of
Each HetA is independently (i) a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from N, O and S, or (ii) quinolinyl, isoquinolinyl And heteroaryl, a heterobicyclic ring selected from quinoxalinyl, wherein the heteroaromatic ring (i) or bicyclic ring (ii) is optionally selected from 1 to 4 Y ^C Where each Y ^C independently has the same definition as X ^B
Each HetB is independently a 4 to 7 membered saturated or unsaturated, non-aromatic heterocycle, at least one carbon atom independently selected from N, O and S and 1 to 4 With heteroatoms, where each S is optionally oxidized to S (O) or S (O) _2, and where a saturated or unsaturated heterocycle is independently halogen, CN , C _1-6 alkyl, OH, oxo, O—C _1-6 alkyl, C _1-6 haloalkyl, O—C _1-6 haloalkyl, C (O) NH ₂ , C (O) N (H) —C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) H, C (O) —C _1-6 alkyl, CO ₂ H, CO ₂ —C _1-6 alkyl, SO ₂ H or _SO 2 _{-C 1-6} 1 from 4 substituents are alkyl, Is optionally substituted.

  Other embodiments, aspects and features of the invention are further described in, or are apparent from, the description, examples and appended claims that follow.

(Detailed description of the invention)
The present invention includes compounds of formula I as described above and pharmaceutically acceptable salts thereof. Compounds encompassed by Formula I include compounds that are HIV protease inhibitors, and other compounds that can be metabolized in vivo to become HIV protease inhibitors. More specifically, a compound of formula I wherein R ² is CH (R ^J ) -OR ^P is considered to be a prodrug that is converted into a pharmaceutical active ingredient in vivo. Examples of the conversion of prodrugs in vivo include the results of enzyme-catalyzed chemical reactions, metabolic chemical reactions, and / or spontaneous chemical reactions (eg, solvolysis).

  Unless expressly stated to the contrary or clear from the context, the compounds of the invention mean all compounds encompassed by Formula I, whether or not they act as prodrugs.

A first embodiment of the invention (also referred to herein as “Embodiment E1”) is a compound of formula I (alternatively, also referred to simply as “Compound I”), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl substituted with C _1-6 alkyl or C _3-6 cycloalkyl, and all other variables are as originally defined (i.e., in the summary of the invention As defined for compound I).

A second embodiment of the invention (Embodiment E2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl, C _1-6 fluoroalkyl, C _{3 -5} cycloalkyl or _CH 2 _{-C 3-5} cycloalkyl, and all other variables are as originally defined.

A third embodiment of the invention (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , _{CH 2 CH 2 CH 3, CH} 2 CH (CH 3) 2, CH 2 CH 2 CH (CH 3) 2, CH 2 CH 2 CH 2 F, cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH _2, - Cyclobutyl and all other variables are as originally defined.

A fourth embodiment of the invention (Embodiment E4) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , _{CH 2 CH 2 CH 3, CH} 2 CH (CH 3) 2, CH 2 CH 2 CH (CH 3) 2, CH 2 CH 2 CH 2 F, cyclobutyl or CH _2, - cyclopropyl, also all other The variables are as originally defined.

A fifth embodiment of the invention (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl, and all other variables are initially As defined.

A sixth embodiment of the invention (Embodiment E6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ Or CH ₂ CH ₂ CH (CH ₃ ) ₂ and all other variables are as originally defined.

A seventh embodiment (embodiment E7) of this part of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₂ CH (CH ₃ ) ₂ or CH ₂ CH ₂ CH (CH ₃ ) ₂ and all other variables are as originally defined.

An eighth embodiment of the invention (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH (CH ₃ ) ₂ and all other variables are As defined at the beginning.

A ninth embodiment of the invention (Embodiment E9) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₂ CH (CH ₃ ) ₂ and all other variables. Is as defined at the beginning.

A tenth embodiment of the invention (Embodiment E10) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₂ CH ₂ CH (CH ₃ ) ₂ and all others The variables are as defined at the beginning.

An eleventh embodiment of the invention (Embodiment E11) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₂ —Z, CH (CH ₃ ) —Z, or CH (CF ₃ ) —Z (ie, R ^J is H, CH ₃ , or CF ₃ ), where Z is OH, NH ₂ , or OR ^P and where ^RP is P (O) ( OH) ₂ , P (O) (ONa) ₂ , P (O) (OK) ₂ , C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) -pyridyl, or C (O) —C _1-6 alkylene-NH ₂ where:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H, and all other variables are as originally defined or as defined in any of the previous embodiments.

Under the conditions first described for Compound I and described in this embodiment, the present invention includes R ³ , R ⁴ , R ⁵ , and R 2 except that R ² is CH ₂ OH or CH ₂ OR ^P. all of the compounds of formula I R ^5A are all H, ^{R 3} and one of ^{R 4} is H, also ^{R 3} and the other ^{R 4} is any of the compounds of formula I are not H (the ^{R 2} value ), All compounds of formula I in which both R ³ and R ⁴ are H, and one or both of R ⁵ and R ^5A are not H (regardless of the value of R ² ). And all compounds of formula I wherein R ³ and R ⁴ are not both H and both R ⁵ and R ^5A are H (regardless of the value of R ² ). Under this condition, compounds in which R ³ and R ⁴ and / or R ⁵ and R ^5A are not H are excluded.

In one embodiment of embodiment E11, R ³ is H, C _1-4 alkyl, C _1-4 fluoroalkyl, or CH ₂ -C _3-5 cycloalkyl, and R ⁴ is H, C _1-4 alkyl. , _{C 1-4} fluoroalkyl or _CH 2 _{-C 3-5} cycloalkyl,, ^{R 5} is, _{H, C 1-4 alkyl, C 1-4} fluoroalkyl, _{C 1-4} alkyl substituted with OH, C _2-4 alkenyl, C _2-4 alkynyl, C _3-5 cycloalkyl, or CH ₂ -C _3-5 cycloalkyl, and R ^5A is H or C _1-4 alkyl, or R ⁵ and R ^5A together with the carbon atom to which both are attached forms a C _3-5 cycloalkyl.

A twelfth embodiment of the invention (embodiment E12) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₂ OH, CH (CH ₃ ) OH, CH ₂ NH _{2 , CH (CH 3) NH 2} , CH 2 oR P or _{CH (CH} 3), an -OR ^{P, wherein, R} P _{is, P (O) (OH)} 2, P (O) (ONa) 2 Or C (O) CH ₃ with the following exceptions:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H, and all other variables are as originally defined or as defined in any of the previous embodiments.

In one aspect of embodiment E12, R ³ is H or CH ₃ , R ⁴ is H or CH ₃ , and R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl, and R ^5A Is H or CH ₃ , or R ⁵ and R ^5A together with the carbon atom to which they are attached form a C _3-5 cycloalkyl.

A thirteenth embodiment of the invention (Embodiment E13) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ₂ is CH ₂ OH, CH (CH ₃ ) OH, or CH ₂ NH ₂ except that:
(A) when R ² is CH ₂ OH, at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ₃ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H, and all other variables are as originally defined or as defined in any of the previous embodiments.

In one embodiment of embodiment E13, R ³ is H or CH ₃ , R ⁴ is H or CH ₃ , and R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, or cyclopropyl, and R ^5A is H or CH ₃ , but R ^5A is when CH ₃ is ^{R 5} is CH _3, or, ^{R 5} and ^{R 5A} form a cyclobutyl or cyclopentyl together with the carbon atom to which both are bound.

A fourteenth embodiment of the invention (Embodiment E14) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ₂ is CH ₂ OH, provided that:
(A) at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H,
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H, and all other variables are as originally defined or as defined in any of the previous embodiments.

In one aspect of embodiment E14, R ³ is H or CH ₃ , R ⁴ is H or CH ₃ , and R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, or cyclopropyl, and R ^5A is H or CH ₃ , but R ^5A is When CH ₃ , R ⁵ is CH ₃ or R ⁵ and R ^5A together with the carbon atom to which they are attached form cyclobutyl or cyclopentyl.

A fifteenth embodiment of the invention (Embodiment E15) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₂ OH, R ³ is H, and R ⁴ is H R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl , Ethynyl, or cyclopropyl, and R ^5A is H or CH ₃ , but when R ^5A is CH ₃ , R ⁵ is CH ₃ , or R ⁵ and R ^5A are the carbons to which they are attached. forms a cyclobutyl or cyclopentyl together with the atom, provided that, R ⁵ and either or both are not H of R ^5A, also all other variables are either as originally defined, or of the foregoing embodiments It is as defined or Chidore.

A sixteenth embodiment of the invention (Embodiment E16) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is:

であり、
Ｒ^６Ａは、ＨまたはＣ_１−４アルキルで、
あるいは、Ｒ^６およびＲ^６Ａこれらが結合する炭素とともにフェニルで任意に置換されるＣ_３−５シクロアルキルを形成し、ここでフェニルは、１から２個のＸ^Ｂで任意に置換される、またその他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。

And
R ^6A is H or C _1-4 alkyl,
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached form a C _3-5 cycloalkyl optionally substituted with phenyl, where phenyl is optionally substituted with 1 to 2 X ^B , and All other variables are as originally defined or as defined in any of the previous embodiments.

A seventeenth embodiment (Embodiment E17) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is:

、
Ｒ^６ＡはＨで、あるいは、Ｒ^６およびＲ^６Ａこれらが結合する炭素とともにフェニルで置換されるシクロプロピルを形成し、ここでフェニルは、１から２個のＸ^Ｂで任意に置換され、またその他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。

,
R ^6A is H, or R ⁶ and R ^6A together with the carbon to which they are attached form a cyclopropyl substituted with phenyl, where phenyl is optionally substituted with 1 to 2 X ^B , and others Are as defined at the beginning or as defined in any of the previous embodiments.

An eighteenth embodiment of the invention (Embodiment E18) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is:

で、
Ｒ^６ＡはＨで、あるいは、Ｒ^６およびＲ^６Ａこれらが結合する炭素とともにフェニルで置換したされるシクロプロピルを形成し、またその他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。

so,
R ^6A is H or R ⁶ and R ^6A together with the carbon to which they are attached form a cyclopropyl substituted with phenyl, and all other variables are as originally defined or As defined in any of the embodiments.

A nineteenth embodiment of the invention (Embodiment E19) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is:

。

.

R ^6A is H and all other variables are as originally defined or as defined in any of the previous embodiments. In one embodiment of this embodiment, m and n are either 0 or both 1, and X ^B and X ^C are (i) both F and both para substituents, (ii) both F and both are meta substituents, or (iii) both are Cl and both are para substituents.

A twentieth embodiment of the present invention (embodiment E20) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein each X ^B and each X ^{C in} the definition of R ⁶ is Independently selected from the group comprising.

(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl,
(18) CH ₂ OH, and (19) CH ₂ O—C _1-3 alkyl,
m is an integer equal to 0, 1 or 2; n is an integer equal to 0, 1 or 2; and all other variables are as originally defined or of the preceding embodiments As defined in one of them. In one aspect of this embodiment, R ⁶ is

で、またＲ^６ＡはＨである。

And R ^6A is H.

A twenty-first embodiment (Embodiment E21) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each X ^B and each X ^{C in} the definition of R ⁶ are: Independently selected from the group comprising.

(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
m is an integer equal to 0, 1, or 2, n is an integer equal to 0, 1, or 2, and all other variables are as originally defined or any of the previous embodiments As defined in. In one embodiment of embodiment E21, m is 0 or 1, and n is 0 or 1. In a further aspect of embodiment E21, R ⁶ is

で、ｍは０または１で、ｎは０または１である。

Where m is 0 or 1 and n is 0 or 1.

A twenty-second embodiment (Embodiment E22) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each X ^A is independently:
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl, or (18) C _1-3 alkyl substituted with (a) cyclopropyl,
(B) CF ₃ ,
(C) OH,
(D) O—C _1-3 alkyl,
(E) OCF ₃ ,
(F) Cl,
(G) Br,
(H) F,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) -C _1-3 alkyl,
(M) N (—C _1-3 alkyl) ₂ ,
(N) C (O) —C _1-3 alkyl,
(O) CO ₂ H, or (p) C (O) O—C _1-3 alkyl,
k is an integer equal to 0, 1, or 2,
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbon atoms to which they are attached. Together with a 5- or 6-membered saturated or unsaturated heterocycle fused to a phenyl ring, wherein the heterocycle contains 1 to 2 independently selected from N, O and S Contains heteroatoms,
All other variables are as defined at the beginning or as defined in any of the previous embodiments.

A twenty-third embodiment (Embodiment E23) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each X ^A is independently:
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH,
(17) CH ₂ OCH ₃ ,
₍₁₈₎ CH 2 _NH 2,
_{(19) CH 2 N (H} ) CH 3,
_{(20) CH 2 N (CH} 3) 2,
(21) CH (CH ₃ ) OH,
(22) CH (CH ₃ ) OCH ₃ ,
(23) CH (CH ₃ ) NH ₂ ,
(24) CH (CH ₃ ) N (H) CH ₃ , or (25) CH (CH ₃ ) N (CH ₃ ) ₂ ,
K is an integer equal to 0, 1 or 2;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms form a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains heteroatoms,
All other variables are as defined at the beginning or as defined in any of the previous embodiments.

A twenty-fourth embodiment (Embodiment E24) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each X ^A is a group (1) to (25) as described in Embodiment E23. ), K is 0 or 1, and all other variables are as originally defined or as defined in any of the previous embodiments.

25th embodiment of the present invention (Embodiment E25) is a compound of Formula I, or a salt thereof acceptable as a pharmaceutical, wherein there are one or two X ^A group phenylsulfonyl moiety, one wherein X ^A in the para position of the phenyl ring and CH ₃ , Cl, Br, F, NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH, and on the other hand, Optional X ^A is in the meta position of the phenyl ring and is Cl, Br, or F;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms, it forms a thiazole fused to the phenyl ring.

が提供される、
またその他すべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。

Provided,
All other variables are as defined at the beginning or as defined in any of the previous embodiments.

A twenty sixth embodiment (Embodiment E26) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, C _1-6 alkyl, C (O) —C _{1 -6} alkyl, C (O) O-C _1-6 alkyl, C (O) N (-C _1-6 alkyl) ₂ , C (O) -HetA, C (O) OCH ₂ -HetA, C (O ) -HetB or _{C (O) OCH 2 -HetB,} , also all other variables, either as originally defined or as defined in any of the aforementioned embodiments.

A twenty seventh embodiment (Embodiment E27) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, C (O) —C _1-6 alkyl, C ( O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) —HetA, or C (O) —HetB, and all other variables are first Or as defined in any of the previous embodiments.

A twenty eighth embodiment (Embodiment E28) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, CH ₃ , C (O) CH ₃ , C (O ) OCH ₃ , C (O) OC (CH ₃ ) ₃ , C (O) N (CH ₃ ) ₂ , C (O) -morpholinyl, C (O) -pyridyl, or C (O) O—CH ₂ — Pyridyl and all other variables are as originally defined or as defined in any of the previous embodiments.

A twenty-ninth embodiment (Embodiment E29) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, C (O) CH ₃ , C (O) OCH ₃ , C (O) N (CH ₃ ) ₂ , C (O) -pyridyl, or C (O) -morpholinyl, and all other variables are as originally defined, or of the previous embodiments As defined in one of them.

A thirtieth embodiment of the invention (Embodiment E30) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, CH ₃ , C (O) OCH ₃ , C (O ) OC (CH ₃ ) ₃ , or C (O) O—CH ₂ -pyridyl, and all other variables are as originally defined or defined in any of the previous embodiments. It is as follows.

A thirty first embodiment (Embodiment E31) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H or C (O) O—C _1-4 alkyl, All other variables are as originally defined or as defined in any of the previous embodiments.

A thirty second embodiment (Embodiment E32) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H or C (O) OCH ₃ and all other variables. Is as initially defined or as defined in any of the previous embodiments.

A thirty third embodiment (Embodiment E33) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is C (O) OCH ₃ and all other variables are As defined initially or as defined in any of the previous embodiments.

A thirty fourth embodiment (Embodiment E34) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H or C _1-4 alkyl, and all other variables. Is as initially defined or as defined in any of the previous embodiments.

A thirty-fifth embodiment of the invention (embodiment E35) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H or CH ₃ and all other variables are Or as defined in any of the previous embodiments.

A thirty sixth embodiment (Embodiment E36) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, and all other variables are as originally defined. Or as defined in any of the previous embodiments.

A thirty seventh embodiment (Embodiment E37) of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Each AryA is independently aryl, which is phenyl or naphthyl, where phenyl or naphthyl is optionally substituted with 1 to 3 substituents, each of which is independently C _1-4 alkyl, CF ₃ , CH ₂ CF ₃ , OH, O—C _1-4 alkyl, OCF ₃ , OCH ₂ CF ₃ , Cl, Br, F, CN, NH ₂ , N (H) —C _1-4 alkyl, N (—C _{1-4 alkyl) 2, CH (O),} C (O) -C 1-4 _{alkyl, CO 2 H, C (O} ) O-C 1-4 alkyl, _SO 2 H or _SO 2 _{-C, 1- 4} alkyl,
Each HetA is independently thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, and quinolinyl. A heteroaryl selected from the group consisting of wherein the heteroaryl is optionally substituted with 1 to 3 substituents, each of which is independently C _1-4 alkyl, CF ₃ , CH ₂ CF ₃ , OH, O—C _1-4 alkyl, OCF ₃ , OCH ₂ CF ₃ , Cl, Br, F, CN, NH ₂ , N (H) —C _1-4 alkyl, N (—C _1-4 alkyl _{) 2, CH (O),} C (O) -C 1- _{Alkyl, CO 2 H, C (O} ) O-C 1-4 alkyl, _SO 2 H or _SO 2 _{-C 1-4} alkyl, and each HetB, independently of, N, O and S A independently selected 5- or 6-membered saturated heterocycle containing 1 to 2 heteroatoms, wherein each S atom is optionally oxidized to S (O) or S (O) ₂ ; Also here, the saturated heterocycle is optionally substituted with 1 to 3 substituents, each independently of C _1-4 alkyl, oxo, C (O) NH ₂ , C (O) N (H). -C _{1-4 alkyl, C (O) N (-C} 1-4 _{alkyl) 2, CH (O),} C (O) -C 1-4 _{alkyl, CO 2 H, C (O} ) O-C 1 _-4 alkyl, _SO 2 H or _SO 2 _{-C 1-4} alkyl,
All other variables are as originally defined or as defined in any of the previous embodiments.

A thirty-eighth embodiment of the present invention (Embodiment E38) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
Each AryA is independently phenyl, optionally substituted with 1 to 3 substituents, each of which is independently CH ₃ , CF ₃ , OH, OCH ₃ , OCF ₃ , Cl, Br, F, CN, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , CH (O), C (O) CH ₃ , C (O) OCH ₃ , or SO ₂ CH ₃ ,
Each HetA is independently a heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, and quinoxalinyl, wherein the heteroaryl is 1 to 3 substituents Each optionally substituted, each independently CH ₃ , CF ₃ , OH, OCH ₃ , OCF ₃ , Cl, Br, F, CN, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , CO ₂ CH ₃ , or SO ₂ CH ₃ , and each HetB is independently selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl in the the saturated heterocyclic ring, the S is optionally oxidized to S (O) or S (O) _2, or Wherein the ring is optionally substituted with one or two substituents, that at each occurrence independently _CH 3, _CH 2 CH _{3, oxo, C (O) N (CH} 3) 2, C (O) CH ₃ , CO ₂ CH ₃ , or S (O) ₂ CH ₃ ,
All other variables are as defined at the beginning or as defined in any of the previous embodiments.

  A thirty ninth embodiment (Embodiment E39) of the invention is a compound of formula II.

、
または医薬品として容認できるその塩で、ここですべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。

,
Or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined or as defined in any of the previous embodiments.

  A 40th embodiment of the invention (Embodiment E40) is a compound of formula III.

、
または医薬品として容認できるその塩で、ここでＲ^５はＣ_１−６アルキル、Ｃ_１−６フルオロアルキル、ＯＨで置換したＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルで、その他すべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりであるが、ただしＲ^３とＲ^４のうち少なくとも１つはＨである。本実施形態の一様態において、Ｒ^２はＣＨ_２ＯＨで、Ｒ^３はＨで、Ｒ^４はＨで、Ｒ^７はＣ（Ｏ）ＯＣＨ_３で、またＲ^８はＨである。

,
Or a salt thereof acceptable as a pharmaceutical, wherein ^{R 5} is _{C 1-6 alkyl, C 1-6} fluoroalkyl, _{C 1-6} alkyl substituted with _{OH, C 2-6 alkenyl, C 2-6} alkynyl, C _3-6 cycloalkyl or C _3-6 C _1-6 alkyl substituted with cycloalkyl, and all other variables are either as was originally defined or as defined in any of the aforementioned embodiments With the proviso that at least one of R ³ and R ⁴ is H. In one aspect of this embodiment, R ² is CH ₂ OH, R ³ is H, R ⁴ is H, R ⁷ is C (O) OCH ₃ , and R ⁸ is H.

  A forty-first embodiment (Embodiment E41) of the invention is a compound of formula IV:

、
または医薬品として容認できるその塩で、ここでＲ^５は、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、ＯＨで置換したＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルで、またその他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。本実施形態の一様態において、Ｒ^５は、ＣＨ_３、ＣＨ_２ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ_２ＣＨ_３、Ｃ（ＣＨ_３）_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＣＨ_２ＯＨ、エテニル、エチニル、シクロプロピル、シクロブチル、ＣＨ_２−シクロプロピル、またはＣＨ_２−シクロブチルである。別の面において、Ｒ^５は、ＣＨ_３、ＣＨ_２ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ_２ＣＨ_３、Ｃ（ＣＨ_３）_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＣＨ_２ＯＨ、エテニル、エチニル、またはシクロプロピルである。本実施形態の別の面において、Ｒ^２はＣＨ_２ＯＨで、またＲ^７はＣ（Ｏ）ＯＣＨ_３である。

,
Or a salt thereof acceptable as a pharmaceutical, wherein ^{R 5} is _{C 1-6 alkyl, C 1-6} fluoroalkyl, _{C 1-6} alkyl substituted with _{OH, C 2-6 alkenyl, C 2-6} alkynyl, C _1-6 cycloalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl, and all other variables are as originally defined, or any of the previous embodiments As defined in. In one embodiment of this embodiment, R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH ₂ - is cyclobutyl. In another aspect, R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, Ethenyl, ethynyl, or cyclopropyl. In another aspect of this embodiment, R ² is CH ₂ OH and R ⁷ is C (O) OCH ₃ .

  A forty-second embodiment (Embodiment E42) of the invention is a compound of formula V:

または医薬品として容認できるその塩で、ここでＲ^５は、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、ＯＨで置換したＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルで、またその他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりである。本実施形態の一様態において、Ｒ^５は、ＣＨ_３、ＣＨ_２ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ_２ＣＨ_３、Ｃ（ＣＨ_３）_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＣＨ_２ＯＨ、エテニル、エチニル、シクロプロピル、シクロブチル、ＣＨ_２−シクロプロピル、またはＣＨ_２−シクロブチルである。別の面において、Ｒ^５は、ＣＨ_３、ＣＨ_２ＣＨ_３、ＣＨ（ＣＨ_３）_２、ＣＨ_２ＣＨ_２ＣＨ_３、Ｃ（ＣＨ_３）_３、ＣＦ_３、ＣＦ_２ＣＦ_３、ＣＨ_２ＯＨ、エテニル、エチニル、またはシクロプロピルである。

Or a salt thereof acceptable as a pharmaceutical, wherein ^{R 5} is _{C 1-6 alkyl, C 1-6} fluoroalkyl, _{C 1-6} alkyl substituted with _{OH, C 2-6 alkenyl, C 2-6} alkynyl, C _1-6 cycloalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl, and all other variables are as originally defined, or any of the previous embodiments As defined in. In one embodiment of this embodiment, R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH ₂ - is cyclobutyl. In another aspect, R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, Ethenyl, ethynyl, or cyclopropyl.

  A forty-third embodiment (Embodiment E43) of the invention is a compound of formula VI:

、
または医薬品として容認できるその塩で、ここでＲ^５はＣ_１−６アルキル、Ｃ_１−６フルオロアルキル、ＯＨで置換したＣ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−６シクロアルキル、またはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルで、その他のすべての変数は、最初に定義したとおりであるか、または前述の実施形態のうちどれかで定義したとおりであるが、ただしＲ^３とＲ^４のうち少なくとも１つはＨである。本態様の一様態において、Ｒ^２はＣＨ_２ＯＨ、Ｒ^３はＨ、Ｒ^４はＨ、Ｒ^７はＣ（Ｏ）ＯＣＨ_３、およびＲ^８はＨである。

,
Or a salt thereof acceptable as a pharmaceutical, wherein ^{R 5} is _{C 1-6 alkyl, C 1-6} fluoroalkyl, _{C 1-6} alkyl substituted with _{OH, C 2-6 alkenyl, C 2-6} alkynyl, C _3-6 cycloalkyl or C _3-6 C _1-6 alkyl substituted with cycloalkyl, and all other variables are defined in any of the first are as defined or the aforementioned embodiments Provided that at least one of R ³ and R ⁴ is H. In one embodiment of this embodiment, R ² is CH ₂ OH, R ³ is H, R ⁴ is H, R ⁷ is C (O) OCH ₃ , and R ⁸ is H.

  A forty-fourth embodiment of the invention (Embodiment E44) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined, provided that:

(A) at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when both R ³ and R ⁴ are not H , R ⁵ and R ^5A are both H.

The E44 condition defines a subset of compounds of the invention in which at least one (but not all) of R ³ , R ⁴ , R ⁵ and R ^5A is not H. More specifically, it is required that (i) R ³ = H, or (ii) R ⁴ = H, or (iii) R ⁵ = R ^5A = H, and R ³ , R ⁴ , R ⁵ And at least one of R ^5A is not H. Embodiments of Embodiment E44 include compounds of Formula I, where all variables are as defined in any of the preceding embodiments, except that this condition applies to it, provided that Otherwise, provided that a subset of the compounds included in this embodiment is defined.

The first class of compounds of the present invention (or referred to herein as Class C1) includes compounds of Formula I, and pharmaceutically acceptable salts thereof, where:
R ¹ is C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-5 cycloalkyl, or CH ₂ -C _3-5 cycloalkyl,
R ² is CH ₂ —Z, CH (CH ₃ ) —Z, CH (CF ₃ ) —Z, where Z is OH, NH ₂ , or OR ^P , where ^RP is P (O ) (OH) ₂ , P (O) (ONa) ₂ , P (O) (OK) ₂ , C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O ) N (—C _1-6 alkyl) ₂ , C (O) -pyridyl, or C (O) —C _1-6 alkylene-NH ₂ ;
R ³ is H, C _1-4 alkyl, C _1-4 fluoroalkyl, or CH ₂ -C _3-5 cycloalkyl,
R ⁴ is H, C _1-4 alkyl, C _1-4 fluoroalkyl, or CH ₂ -C _3-5 cycloalkyl,
R ⁵ is, _{H, C 1-4 alkyl, C 1-4} fluoroalkyl, _{C 1-4} alkyl substituted with _{OH, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5} cycloalkyl or CH, _2- C _3-5 cycloalkyl,
R ^5A is H or C _1-4 alkyl,
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-5 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H.
R ⁶ is:

であり、ここで星印（＊）は、化合物の他の部分への結合点を示す、
Ｒ^６Ａは、ＨまたはＣ_１−４アルキルで、
あるいは、Ｒ^６およびＲ^６Ａこれらが結合する炭素とともにフェニルで任意に置換されるＣ_３−５シクロアルキルを形成し、ここでフェニルは、１から２個のＸ^Ｂで任意に置換され、
それぞれのＸ^ＢおよびそれぞれのＸ^Ｃは、以下で構成される群から独立的に選択される。

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
R ^6A is H or C _1-4 alkyl,
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached form a C _3-5 cycloalkyl optionally substituted with phenyl, where the phenyl is optionally substituted with 1 to 2 X ^B ;
Each ^XB and each ^XC is independently selected from the group consisting of:

(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl,
(18) CH ₂ OH, and (19) CH ₂ O—C _1-3 alkyl,
m is an integer equal to 0, 1, or 2,
n is an integer equal to 0, 1, or 2,
Each of ^{X A} is, independently:
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl, or (18) C _1-3 alkyl substituted with (a) cyclopropyl,
(B) CF ₃ ,
(C) OH,
(D) O—C _1-3 alkyl,
(E) OCF ₃ ,
(F) Cl,
(G) Br,
(H) F,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) -C _1-3 alkyl,
(M) N (—C _1-3 alkyl) ₂ ,
(N) C (O) —C _1-3 alkyl,
(O) CO ₂ H, or (p) C (O) O—C _1-3 alkyl,
k is an integer equal to 0, 1, or 2,
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms form a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains heteroatoms,
R ⁷ is H, C _1-6 alkyl, C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , _{C (O) -HetA, C (} O) OCH 2 -HetA, C (O) -HetB , or _{C (O) OCH 2 -HetB,} ,
R ⁸ is H or C _1-4 alkyl,
HetA is a heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, and quinoxalinyl, wherein the heteroaryl is optionally substituted with 1 to 3 substituents, Each is independently CH ₃ , CF ₃ , OH, OCH ₃ , OCF ₃ , Cl, Br, F, CN, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , CO ₂ CH ₃ , or SO ₂ CH ₃ , and HetB are saturated heterocycles selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, where S is S (O ) or S (O) ₂ optionally be oxidized, and any location wherein the ring by one or two substituents In is, its at each occurrence independently _CH 3, _CH 2 CH _{3, oxo, C (O) N (CH} 3) 2, C (O) CH 3, CO 2 CH 3 or S _(O) 2 CH _3, is there.

The first subclass of class C1 (subclass SC1-1) includes compounds of formula I and their pharmaceutically acceptable salts, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ Is H, but one or both of R ⁵ and R ^5A are not H, R ^6A is H, R ⁷ is C (O) OCH ₃ and R ⁸ is H, and all other variables Is as first defined in class C1.

A second class of compounds of the invention (Class C2) includes compounds of Formula I, and pharmaceutically acceptable salts thereof, where:
R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ F, cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH _2, - cyclobutyl,
R ² is CH ₂ OH, CH (CH ₃ ) OH, CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH ₂ OR ^P , or CH (CH ₃ ) —OR ^P where R ^P is P (O) (OH) ₂ , P (O) (ONa) ₂ , or C (O) CH ₃ ,
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl , cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH _2, - cyclobutyl,
R ^5A is H or CH ₃
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-5 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H.
R ⁶ is:

、
Ｒ^６ＡはＨで、
あるいは、Ｒ^６およびＲ^６Ａこれらが結合する炭素とともにフェニルで置換されるシクロプロピルを形成し、ここでフェニルは、１から２個のＸ^Ｂで任意に置換される、
それぞれのＸ^ＢおよびそれぞれのＸ^Ｃは、以下で構成される群から独立的に選択される。

,
R ^6A is H,
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached form a cyclopropyl substituted with phenyl, where the phenyl is optionally substituted with 1 to 2 X ^B.
Each ^XB and each ^XC is independently selected from the group consisting of:

(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
m is 0, 1 or 2,
n is 0, 1, or 2,
Each of ^{X A} is, independently:
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH,
(17) CH ₂ OCH ₃ ,
₍₁₈₎ CH 2 _NH 2,
_{(19) CH 2 N (H} ) CH 3,
_{(20) CH 2 N (CH} 3) 2,
(21) CH (CH ₃ ) OH,
(22) CH (CH ₃ ) OCH ₃ ,
(23) CH (CH ₃ ) NH ₂ ,
(24) CH (CH ₃ ) N (H) CH ₃ , or (25) CH (CH ₃ ) N (CH ₃ ) ₂ ,
k is 0, 1, or 2,
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms form a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains heteroatoms,
R ⁷ is H, CH ₃ , C (O) CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , C (O) N (CH ₃ ) ₂ , C (O) — Morpholinyl, C (O) -pyridyl, or C (O) O—CH ₂ -pyridyl, and R ⁸ is H or CH ₃ .

The first subclass of class C2 (subclass SC1-2) includes compounds of formula I and pharmaceutically acceptable salts thereof, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ Is H, but one or both of R ⁵ and R ^5A are not H, R ^6A is H, R ⁷ is C (O) OCH ₃ and R ⁸ are H, and all other variables Is as first defined in class C2.

Class C2 second subclass (subclass SC2-2) compounds of formula III and pharmaceutically acceptable salts thereof, wherein R ₃ is H or CH ₃ and R ⁴ is H or CH ₃ However, at least one of R ³ and R ⁴ is H, and R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF _{3, CF 2 CF 3, CH} 2 OH, ethenyl, ethynyl, cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH _2, - ^{cyclobutyl, R 5A} is ^H, with ^{R 6A} is H, also in all other The variables are as originally defined in class C2.

The third subclass of class C2 (subclass SC3-2) includes compounds of formula III and their pharmaceutically acceptable salts, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ is H, R ⁷ is C (O) OCH ₃ and R ⁸ is H, and all other variables are as originally defined in subclass SC2-2.

A third class of compounds of the invention (Class C3) includes compounds of Formula I, and pharmaceutically acceptable salts thereof, where:
R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ F, cyclobutyl or CH _2, - cyclopropyl,
R ² is CH ₂ OH, CH (CH ₃ ) OH, or CH ₂ NH ₂ ,
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl Or cyclopropyl,
R ^5A is H or CH ₃ , but when R ^5A is CH ₃ , R ⁵ is CH ₃ ;
Alternatively, R ⁵ and R ^5A together with the carbon atom to which they are attached form cyclobutyl or cyclopentyl,
However:
(A) when R ² is CH ₂ OH, at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) when either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H, and (C) when R ³ and R ⁴ are not both H, R ⁵ and R ^5A are both H.
R ⁶ is:

で、
Ｒ^６ＡはＨで、
あるいは、Ｒ^６およびＲ^６Ａは、それらが結合する炭素とともにフェニルで置換したされるシクロプロピルを形成し、
フェニルスルホニル部分に１個または２個のＸ^Ａ基があり、ここで一方のＸ^Ａはフェニル環のパラ位置にあり、かつＣＨ_３、Ｃｌ、Ｂｒ、Ｆ、ＮＨ_２、Ｃ（Ｏ）ＣＨ_３、ＣＨ_２ＯＨ、またはＣＨ（ＣＨ_３）ＯＨで、また他方の任意的なＸ^Ａはフェニル環のメタ位置にあり、かつＣｌ、Ｂｒ、またはＦで、
あるいは、２つのＸ^Ａ置換基がフェニル環に存在し、および２つのＸ^Ａがフェニル環の隣接した炭素原子に結合しているときには、その２つのＸ^Ａはそれらが結合している炭素原子とともに、フェニル環に融合されたチアゾールを形成し

so,
R ^6A is H,
Alternatively, R ⁶ and R ^6A form a cyclopropyl substituted with phenyl with the carbon to which they are attached,
There are one or two X ^A groups in the phenylsulfonyl moiety, where one X ^A is in the para position of the phenyl ring and CH ₃ , Cl, Br, F, NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH, and the other optional X ^A is in the meta position of the phenyl ring and is Cl, Br, or F,
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A together with the carbon atom to which they are attached Form thiazole fused to the phenyl ring

が提供される、
Ｒ^７はＨ、ＣＨ_３、Ｃ（Ｏ）ＯＣＨ_３、Ｃ（Ｏ）ＯＣ（ＣＨ_３）_３、またはＣ（Ｏ）Ｏ−ＣＨ_２−ピリジルで、ならびに
Ｒ^８はＨまたはＣＨ_３である。

Provided,
R ⁷ is H, CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , or C (O) O—CH ₂ -pyridyl, and R ⁸ is H or CH ₃ .

The first subclass of class C3 (subclass SC _1-3 ) includes compounds of formula I and pharmaceutically acceptable salts thereof, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ Is H, where one or both of R ⁵ and R ^5A are not H, R ^6A is H, R ⁷ is C (O) OCH ₃ and R ⁸ is H, and all other variables are , As first defined in class C3.

The second subclass of class C3 (subclass SC2-3) includes compounds of formula III and their pharmaceutically acceptable salts, wherein R ³ is H or CH ₃ and R ⁴ is H or CH ₃ However, at least one of R ³ and R ⁴ is H, and R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF _{3, CF 2 CF 3, CH} 2 OH, ethenyl, ethynyl or ^{cyclopropyl,, R 5A} is ^{H, R 6A} is H, also all other variables are as originally defined in class C3.

The third subclass of class C3 (subclass SC3-3) includes compounds of formula III and their pharmaceutically acceptable salts, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ Is H, R ⁷ is C (O) OCH ₃ and R ⁸ is H, and all other variables are as originally defined in subclass SC2-3.

A fourth class of compounds of the invention (Class C4) includes compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R ² is CH ₂ OH, R ³ is H, R ⁴ Is H, where one or both of R ⁵ and R ^5A are not H, R ^6A is H, R ⁷ is C (O) OCH ₃ and R ⁸ is H, and all other variables are As defined at the beginning.

A fifth class of compounds of the invention (Class C5) includes compounds of Formula V, and pharmaceutically acceptable salts thereof, where:
R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ F, cyclobutyl or CH _2, - cyclopropyl,
R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, or Cyclopropyl,
X ^A is NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH,
Each ^XB and each ^XC is independently selected from the group consisting of:

(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
m is an integer equal to 0, 1, or 2,
n is an integer equal to 0, 1, or 2,
The first subclass of class C5 (subclass SC1-5) includes compounds of formula V and pharmaceutically acceptable salts thereof, wherein R ¹ is CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ , or CH ₂ CH ₂ CH (CH ₃ ) ₂ , and all other variables are as originally defined in class C5.

The second subclass of class C5 (subclass SC2-5) includes compounds of formula V and pharmaceutically acceptable salts thereof, where m and n are either 0 or both 1 And X ^B and X ^C are (i) both F and both para substituents, (ii) both F and both meta substituents, or (iii) both Cl and both para substituents, And all other variables are as originally defined in class C5.

The third subclass of class C5 (subclass SC3-5) includes compounds of formula V and their pharmaceutically acceptable salts, wherein R ¹ is CH (CH ₃ ) ₂ , CH ₂ CH (CH _{3) 2,} or _CH 2 _CH 2 CH _{(CH 3) 2,} and all variables other, are as originally defined subclasses SC2-5.

  A forty-fifth embodiment (Embodiment E45) of this part of the invention is a compound selected from the group consisting of the compounds described in Examples A1 to M1 (including the first and last) and also as a medicament It is an acceptable salt.

  A 46th embodiment (Embodiment E46) of this part of the invention consists of the group consisting of the compounds described in Examples D2, E1, F1, F2, H1, H3, J1, J27, K1, K4, L2. And a pharmaceutically acceptable salt thereof.

  The present invention also includes compounds of formula IA.

、
および医薬品として容認できるそれらの塩で、ここで：
Ｒ^１は、Ｃ_１−６アルキルまたはＣ_３−６シクロアルキルで置換したＣ_１−６アルキルで、
Ｒ^３は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−５シクロアルキルで置換したＣ_１−６アルキルで、
Ｒ^４は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−５シクロアルキルで置換したＣ_１−６アルキルで、
Ｒ^５は、Ｈ、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−５シクロアルキルで置換したＣ_１−６アルキルで、
ただし：
（Ａ）Ｒ^２がＣＨ_２ＯＨまたはＣＨ_２ＯＲ^Ｐのときには、Ｒ^３、Ｒ^４、およびＲ^５のうち少なくとも１つは、Ｃ_１−６アルキル、Ｃ_１−６フルオロアルキル、またはＣ_３−５シクロアルキルで置換したＣ_１−６アルキルで、および
（Ｂ）Ｒ^３、Ｒ^４、およびＲ^５のうち少なくとも１つはＨで、また
それぞれのＸ^Ａは、独立的に、化合物Ｉについて最初に定義したとおりであるか（発明の要約を参照）、
あるいは、２つ以上のＸ^Ａ置換基がフェニル環に存在するとき、かつ２つのＸ^Ａがフェニル環の隣接した炭素原子に結合しているとき、その２つのＸ^Ａは、任意的にまとまって−ＯＣＨ_２Ｏ−または−ＯＣＨ_２ＣＨ_２Ｏ−を形成する、
Ｒ^６は：

,
And their pharmaceutically acceptable salts, where:
R ¹ _is a _{C 1-6} alkyl substituted with _{C 1-6} alkyl or _{C 3-6} cycloalkyl,
R ³ is, _H, by _{C 1-6 alkyl, C 1-6} fluoroalkyl _{C 1-6} alkyl or substituted with _{C 3-5} cycloalkyl,
R ⁴ is, _H, by _{C 1-6 alkyl, C 1-6} fluoroalkyl _{C 1-6} alkyl or substituted with _{C 3-5} cycloalkyl,
R ⁵ is, _H, by _{C 1-6 alkyl, C 1-6} fluoroalkyl _{C 1-6} alkyl or substituted with _{C 3-5} cycloalkyl,
However:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is C _1-6 alkyl, C _1-6 fluoroalkyl, or C _3- C _1-6 alkyl substituted with ₅ cycloalkyl, and (B) at least one of R ³ , R ⁴ , and R ⁵ is H, and each X ^A is independently first for compound I (See summary of invention),
Alternatively, when two or more X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are optionally grouped together Form —OCH ₂ O— or —OCH ₂ CH ₂ O—,
R ⁶ is:

、ここで星印（＊）は、化合物の他の部分への結合点を示す、および
Ｒ^Ｋは：
（１）Ｃ_１−６アルキル、
（２）Ｃ_３−６シクロアルキル、
（３）Ｃ_３−６シクロアルキルで置換したＣ_１−６アルキル、
（４）Ｏ−Ｃ_１−６アルキル、
（５）Ｏ−Ｃ_１−６アルキルで置換したＯ−Ｃ_１−６アルキル、
（６）Ｏ−Ｃ_１−６フルオロアルキル、
（７）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキル、
（８）Ｃ（Ｏ）Ｏ−Ｃ_１−６アルキルで置換したＣ_１−６アルキル、
（９）Ｃ（Ｏ）ＯＨで置換したＣ_１−６アルキル、
（１０）Ｃ（Ｏ）−Ｃ_１−６アルキルで置換したＣ_１−６アルキル、
（１１）Ｎ（Ｈ）−Ｃ_１−６アルキル、
（１２）Ｎ（−Ｃ_１−６アルキル）_２、
（１３）ＮＨ_２、Ｎ（Ｈ）−Ｃ_１−６アルキル、またはＮ（−Ｃ_１−６アルキル）_２で置換したＣ_１−６アルキル、
（１４）ＡｒｙＡ、
（１５）ＡｒｙＡで置換したＣ_１−６アルキル、
（１６）ＡｒｙＡで置換したＯ−Ｃ_１−６アルキル、
（１７）ＨｅｔＡ、
（１８）ＨｅｔＡで置換したＣ_１−６アルキル、
（１９）ＨｅｔＡで置換したＯ−Ｃ_１−６アルキル、
（２０）ＨｅｔＢ、または
（２１）Ｏ−ＨｅｔＢ、
またその他すべての変数は最初に定義したとおりである（すなわち、本発明の要約で化合物Ｉについて定義したとおり）。

Where the asterisk (*) indicates the point of attachment to the other part of the compound, and ^RK is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(9) C _1-6 alkyl substituted with C (O) OH,
(10) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(11) N (H) -C _1-6 alkyl,
(12) N (—C _1-6 alkyl) ₂ ,
(13) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(14) AryA,
(15) C _1-6 alkyl substituted with AryA,
(16) O—C _1-6 alkyl substituted with AryA,
(17) HetA,
(18) C _1-6 alkyl substituted with HetA,
(19) O—C _1-6 alkyl substituted with HetA,
(20) HetB, or (21) O-HetB,
All other variables are as originally defined (ie, as defined for Compound I in the summary of the invention).

A first embodiment of this part of the invention (also referred to herein as “Embodiment E1-A”) is a compound of formula IA (alternatively also referred to as “Compound IA”) Or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl, and all other variables are as previously defined for the compound of formula IA.

A second embodiment of this part of the invention (embodiment E2-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₂ CH (CH ₃ ) ₂ or in _{CH 2 CH 2 CH (CH 3} ) 2, also all other variables are as originally defined for compound I-a.

A third embodiment (embodiment E3) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CH ₂ CH ₂ CH (CH ₃ ) ₂ And all other variables are as originally defined for Compound IA.

A fourth embodiment of this part of the invention (embodiment E4-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₂ —Z, CH (CH ₃ ) -Z, in CH _(CF 3) -Z, wherein Z is a OH, NH ₂ or oR ^P,, also where ^R P _{is, P (O) (OH)} 2, P (O) (ONa ) ₂ , P (O) (OK) ₂ , C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) -pyridyl, or C (O) -C _1-6 alkylene-NH ₂ where:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is C _1-6 alkyl, C _1-6 fluoroalkyl, or C _3- C _1-6 alkyl substituted with ₅ cycloalkyl, and (B) at least one of R ³ , R ⁴ , and R ⁵ is H,
All other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

Under the conditions initially described for compound IA and the conditions described in this embodiment, the present invention includes that R ³ , R ⁴ , and R ⁵ are all H and R ² is CH ₂ OH or CH ₂ OR. Except for compounds that are ^P , all compounds of formula IA, R ³ , R ⁴ , and R ⁵ , all compounds of formula I where two are H and the others are not H, and R ³ , R ⁴ , And all compounds in which one of R ⁵ is H and the other two are not H.

A fifth embodiment (embodiment E5-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ³ is H or C _1-4 alkyl, R ⁴ is H or C _1-4 alkyl and R ⁵ is H or C _1-4 alkyl, provided that:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is C _1-4 alkyl, and (B) R ³ , R ⁴ , And at least one of R ⁵ is H,
All other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

In one aspect of embodiment E5-A, one of R ³ , R ^4, and R ⁵ is C _1-4 alkyl, and the other two of R ³ , R ^4, and R ⁵ are H.

A sixth embodiment of this part of the invention (embodiment E6-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ³ is H, CH ₃ , CF ₃ , CH ₂ - cyclopropyl, or CH _2, - cyclobutyl, ^{R 4} _{is, H, CH 3, CF 3} , CH ₂ - cyclopropyl, or CH _2, - cyclobutyl, ^{R 5} _{is, H, CH 3, CF 3} , CH ₂ - cyclopropyl, or CH ₂ - is a cyclobutyl, provided that:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl. And (B) at least one of R ³ , R ⁴ , and R ⁵ is H,
All other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

In one aspect of embodiment E6-A, one of R ³ , R ^4, and R ⁵ is CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl, and R ³ , R ^4, and R 5 The other two of ⁵ are H.

A seventh embodiment of this part of the invention (embodiment E7-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₂ OH, CH (CH ₃ ) _{OH, CH 2 NH 2, CH} (CH 3) NH 2, CH 2 oR P or ^{_{CH (CH 3) -OR P,}} , wherein ^{R P} is _{P (O) (OH) 2} , P (O) ( ONa) ₂ , or C (O) CH ₃ , R ³ is H or CH ₃ , R ⁴ is H or CH ₃ , and R ⁵ is H or CH ₃ , but:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is CH ₃ , and (B) R ³ , R ⁴ , and R ⁵ At least one of them is H.

In an embodiment of embodiment E7-A, one of R ³ , R ^4, and R ⁵ is CH ₃ , the other two of R ³ , R ^4, and R ⁵ are H, and all others Are as defined initially for compound IA or as defined in any one of the previous embodiments for compound IA.

An eighth embodiment of this part of the invention (embodiment E8-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is:

で、またその他すべての変数は化合物Ｉ−Ａについて最初に定義したとおりであるか、または化合物Ｉ−Ａについての前述の実施形態のどれか１つで定義したとおりである。

And all other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

A ninth embodiment of this part of the invention (embodiment E9-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein each X ^{B in} the definition of R ⁶ and each X ^C is independently selected from the group consisting of groups (1) to (19) described in embodiment E20 above, m is an integer equal to 0, 1, or 2 and n is 0, 1, Or an integer equal to 2 and all other variables are as originally defined for Compound IA or as defined in any one of the previous embodiments for Compound IA. In one aspect of embodiment E9-A, R ⁶ is:

である。

It is.

A tenth embodiment of this part of the invention (Embodiment E10-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein each X ^{B in} the definition of R ⁶ and each X ^C is independently selected from the group consisting of groups (1) to (17) described in embodiment E21 above, m is an integer equal to 0 or 1, and n is 0 or 1. With equal integers and all other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA. In one aspect of embodiment E10-A, R ⁶ is:

である。

It is.

An eleventh embodiment (embodiment E11-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein in the definition of R ⁶ , X ^B and X ^C are Both are F, m is 0 or 1, n is 0 or 1, and all other variables are as originally defined for compound IA, or as described above for compound IA. As defined in any one of the embodiments. In one aspect of embodiment E11-A, R ⁶ is:

である。

It is.

A twelfth embodiment of this part of the invention (embodiment E12-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein each X ^A is as defined in embodiment E22 above. Is independently selected from the listed groups (1) to (18), k is an integer equal to 0, 1 or 2 and all other variables are as originally defined for compound IA; Or as defined in any one of the preceding embodiments for Compound IA.

A thirteenth embodiment (embodiment E13-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein each X ^A is as described in embodiment E23 above. Independently selected from groups (1) to (25), k is an integer equal to 0 or 1, and all other variables are as originally defined for compound IA or As defined in any one of the previous embodiments for -A.

A fourteenth embodiment of this part of the invention (embodiment E14-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein k is 0, or k is 1 and X ^A Is para to the sulfonyl and all other variables are as originally defined for compound IA, or any one of the preceding embodiments for compound IA As defined in.

A fifteenth embodiment of this part of the invention (embodiment E15-A) is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein k is 0, or k is 1 and X ^A Is 4-CH ₃ or 4-NH ₂ and all other variables are as originally defined for compound IA or any one of the preceding embodiments for compound IA As defined in.

A sixteenth embodiment (embodiment E16-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, C (O) —C _{1 -6} alkyl, C (O) O-C _1-6 alkyl, C (O) N (-C _1-6 alkyl) ₂ , C (O) -HetA, or C (O) -HetB, and other All variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

A seventeenth embodiment (embodiment E17-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H, C (O) CH ₃ , C (O) OCH ₃ , C (O) N (CH ₃ ) ₂ , C (O) -pyridyl, or C (O) -morpholinyl, and all other variables as originally defined for Compound IA Or as defined in any one of the preceding embodiments for Compound IA.

An eighteenth embodiment (embodiment E18-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H or C (O) O—C _1-4 alkyl, and all other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

A nineteenth embodiment (embodiment E19-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H or C (O) OCH ₃ And all other variables are as originally defined for Compound IA, or as defined in any one of the previous embodiments for Compound IA.

  A twentieth embodiment (embodiment E20-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein AryA, HetA and HetB are as described above in embodiment E37. As defined and all other variables are as originally defined for Compound IA, or as defined in any one of the previous embodiments for Compound IA.

  A twenty-first embodiment (embodiment 21-A) of this part of the invention is a compound of formula IA, or a pharmaceutically acceptable salt thereof, wherein AryA, HetA, and HetB are as described above for embodiment E38. And all other variables are as originally defined for compound IA or as defined in any one of the previous embodiments for compound IA.

  A twenty-second embodiment (Embodiment E22-A) of this part of the invention is a compound of Formula II-A:

、
または、医薬品として容認できるその塩で、ここですべての変数は化合物Ｉ−Ａについて最初に定義したとおりであるか、または化合物Ｉ−Ａについての前述の実施形態のどれか１つで定義したとおりである。

,
Or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined for compound IA or as defined in any one of the preceding embodiments for compound IA. It is.

  A twenty third embodiment (Embodiment E23-A) of this part of the invention is a compound of Formula III-A:

、
または、医薬品として容認できるその塩で、ここですべての変数は化合物Ｉ−Ａについて最初に定義したとおりであるか、または化合物Ｉ−Ａについての前述の実施形態のどれか１つで定義したとおりである。

,
Or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined for compound IA or as defined in any one of the preceding embodiments for compound IA. It is.

  A twenty fourth embodiment (Embodiment E24-A) of this portion of the invention is a compound of Formula IV-A:

、
または、医薬品として容認できるその塩で、ここですべての変数は化合物Ｉ−Ａについて最初に定義したとおりであるか、または化合物Ｉ−Ａについての前述の実施形態のどれか１つで定義したとおりである。

,
Or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined for compound IA or as defined in any one of the preceding embodiments for compound IA. It is.

  A 25th embodiment of this part of the invention (Embodiment E25-A) is a compound of formula VA:

、
または、医薬品として容認できるその塩で、ここですべての変数は化合物Ｉ−Ａについて最初に定義したとおりであるか、または化合物Ｉ−Ａについての前述の実施形態のどれか１つで定義したとおりである。

,
Or a pharmaceutically acceptable salt thereof, wherein all variables are as originally defined for compound IA or as defined in any one of the preceding embodiments for compound IA. It is.

The first class of compounds of this part of the invention (also referred to herein as class C1-A instead) includes compounds of formula IA, and pharmaceutically acceptable salts thereof, where:
R ¹ is C _1-6 alkyl,
R ² is CH ₂ —Z, CH (CH ₃ ) —Z, CH (CF ₃ ) —Z, where Z is OH, NH ₂ , or OR ^P , where ^RP is P (O ) (OH) ₂ , P (O) (ONa) ₂ , P (O) (OK) ₂ , C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O ) N (—C _1-6 alkyl) ₂ , C (O) -pyridyl, or C (O) —C _1-6 alkylene-NH ₂ ;
R ³ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ⁴ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ⁵ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
However:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl. And (B) at least one of R ³ , R ⁴ , and R ⁵ is H.
R ⁶ is:

、ここで星印（＊）は、化合物の他の部分への結合点を示す、
それぞれのＸ^ＢおよびそれぞれのＸ^Ｃは、以下で構成される群から独立的に選択される。

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
Each ^XB and each ^XC is independently selected from the group consisting of:

(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl,
(18) CH ₂ OH, and (19) CH ₂ O—C _1-3 alkyl,
m is an integer equal to 0, 1, or 2,
n is an integer equal to 0, 1, or 2,
Each of ^{X A} is, independently:
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl, or (18) C _1-3 alkyl substituted with (a) cyclopropyl,
(B) CF ₃ ,
(C) OH,
(D) O—C _1-3 alkyl,
(E) OCF ₃ ,
(F) Cl,
(G) Br,
(H) F,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) -C _1-3 alkyl,
(M) N (—C _1-3 alkyl) ₂ ,
(N) C (O) —C _1-3 alkyl,
(O) CO ₂ H, or (p) C (O) O—C _1-3 alkyl, and k is an integer equal to 0, 1, or 2,
R ⁷ is H, C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) —HetA Or C (O) -HetB,
HetA is a heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, and quinoxalinyl, wherein the heteroaryl is optionally substituted with 1 to 3 substituents, Each is independently CH ₃ , CF ₃ , OH, OCH ₃ , OCF ₃ , Cl, Br, F, CN, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , CO ₂ CH ₃ , or SO ₂ CH ₃ , and HetB are saturated heterocycles selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, where S is S (O ) or S (O) ₂ optionally be oxidized, and any location wherein the ring by one or two substituents In is, its at each occurrence independently _CH 3, _CH 2 CH _{3, oxo, C (O) N (CH} 3) 2, C (O) CH 3, CO 2 CH 3 or S _(O) 2 CH _3, is there.

  The first subclass of class C1-A (in this document, instead referred to as subclass SC1-1-A) includes compounds of formula VI-A:

および医薬品として容認できるその塩が含まれ、ここですべての変数はクラスＣ１−Ａで定義したとおりである。

And pharmaceutically acceptable salts thereof, wherein all variables are as defined in class C1-A.

  The second subclass of class C1-A (subclass SC1-2-A) includes compounds of formula VII-A:

および医薬品として容認できるその塩が含まれ、ここですべての変数はクラスＣ１で定義したとおりである。

And pharmaceutically acceptable salts thereof, wherein all variables are as defined in class C1.

The second class of compounds of this part of the invention (class C2-A) include compounds of formula IA, and pharmaceutically acceptable salts thereof, where:
R ¹ is CH ₂ CH (CH ₃ ) ₂ or CH ₂ CH ₂ CH (CH ₃ ) ₂ ,
R ² is CH ₂ OH, CH (CH ₃ ) OH, CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH ₂ OR ^P , or CH (CH ₃ ) —OR ^P where R ^P is P (O) (OH) ₂ , P (O) (ONa) ₂ , or C (O) CH ₃ ,
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is H or CH ₃
However:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is CH ₃ , and (B) R ³ , R ⁴ , and R ⁵ At least one of them is H.
R ⁶ is:

、
それぞれのＸ^ＢおよびそれぞれのＸ^Ｃは、以下で構成される群から独立的に選択される。

,
Each ^XB and each ^XC is independently selected from the group consisting of:

(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
m is an integer equal to 0 or 1,
n is an integer equal to 0 or 1,
Each of ^{X A} is, independently:
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH,
(17) CH ₂ OCH ₃ ,
₍₁₈₎ CH 2 _NH 2,
_{(19) CH 2 N (H} ) CH 3,
_{(20) CH 2 N (CH} 3) 2,
(21) CH (CH ₃ ) OH,
(22) CH (CH ₃ ) OCH ₃ ,
(23) CH (CH ₃ ) NH ₂ ,
(24) CH (CH ₃ ) N (H) CH ₃ , or (25) CH (CH ₃ ) N (CH ₃ ) ₂ ,
k is an integer equal to 0 or 1, and R ⁷ is H, C (O) CH ₃ , C (O) OCH ₃ , C (O) N (CH ₃ ) ₂ , C (O) -pyridyl, Or C (O) -morpholinyl.

  The first subclass of class C2-A (also referred to herein as subclass SC2-1-A) includes compounds of formula VI-A and pharmaceutically acceptable salts thereof, where all variables are As defined in class C2-A.

  The second subclass of class C2-A (subclass SC2-2-A) includes compounds of formula VII-A and pharmaceutically acceptable salts thereof, wherein all variables are as defined in class C2-A. .

  A twenty-sixth embodiment (Embodiment E26-A) of this part of the invention is a compound selected from the group consisting of:

Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-(3-methylbutyl) amino] -6-hydroxy-1-methylhexyl) -amino) -1- ( Diphenylmethyl) -2-oxoethyl] carbamate,
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-2-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} hexylamino ] -2-oxoethyl} carbamate,
(2S) -2-amino-N-((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] -amino} hexyl) -3,3- Diphenylpropanamide,
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) -sulfonyl] amino} hexyl Amino] -2-oxoethyl} carbamate,
(2S) -2-amino-N- {5-[[(4-aminophenyl) sulfonyl]-(3-methylbutyl) amino] -6-hydroxyheptyl} -3,3-diphenylpropanamide,
Methyl [(1S) -2-({6-amino-5-[[(4-aminophenyl) -sulfonyl]-(3-methylbutyl) amino] -hexyl) -amino) -1- (diphenylmethyl) -2 -Oxoethyl] carbamate,
And their pharmaceutically acceptable salts.

  Compounds of formula IA form a subset of the compounds contained in formula I. All explanations referring to compounds of formula I also apply to compounds of formula IA.

  Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, as first defined or defined in any of the previous embodiments, aspects, classes, or subclasses, wherein The compound or salt thereof is in a substantially pure form. As used herein, “substantially pure” is reasonably at least about 60 wt. %, Generally at least about 70 wt. %, Preferably at least about 80 wt. %, More preferably at least about 90 wt. % (Eg, about 90 wt.% To about 99 wt.%), Even more preferably at least about 95 wt. % (Eg, about 95 wt.% To about 99 wt.%, Or about 98 wt.% To 100 wt.%), And most preferably at least about 99 wt. % (Eg 100 wt.%) Of a product comprising a compound of formula I or a salt thereof (eg a product isolated from a reaction mixture producing the compound or salt) means that the compound or salt is constituted To do. The level of compound and salt purity can be determined using standard analytical methods such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and / or mass spectrometry. Where multiple analytical methods are employed and the method provides experimentally significant differences at a given purity level, the method that provides the highest purity level is preferred. A 100% pure compound or salt is one that does not contain detectable impurities as determined by standard analytical methods. The compounds of the present invention have two or more asymmetric centers and exist as a mixture of stereoisomers. It is understood that a substantially pure compound may be a substantially pure mixture of stereoisomers or a substantially pure individual diastereomer or enantiomer.

  Other embodiments of the present invention include the following.

  (A) A pharmaceutical composition comprising an effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

  (B) A pharmaceutical composition comprising a product prepared by combining (eg, formulating) an effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .

  (C) The pharmaceutical composition of (a) or (b), further comprising an effective amount of an anti-HIV drug selected from the group consisting of HIV antiviral drugs, immunomodulating drugs, and anti-infective drugs .

  (D) the pharmaceutical composition of (c), wherein the anti-HIV drug is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, and HIV maturation An antiviral agent selected from the group consisting of inhibitors.

  (E) The pharmaceutical composition of (d), wherein the antiviral agent is selected from the group consisting of an HIV reverse transcriptase inhibitor and an HIV integrase inhibitor.

  (F) (i) a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and (ii) an antiviral selected from the group consisting of HIV antiviral agents, immunomodulators, and antiinfectives In combination with an HIV drug, where the compound I and the anti-HIV drug, respectively, are for the combination of HIV protease inhibition, treatment or prevention of HIV infection, or treatment, prevention, or onset or progression of AIDS An amount that is effective for delay is employed.

  (G) a combination of (f), wherein the anti-HIV drug is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, and HIV maturation inhibitor An antiviral agent selected from the group consisting of:

  (H) The combination of (g), wherein the antiviral agent is selected from the group consisting of an HIV reverse transcriptase inhibitor and an HIV integrase inhibitor.

  (I) A method for inhibiting HIV protease in a subject in need comprising a procedure of administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

  (J) a method for preventing or treating HIV (eg, HIV-1) infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. What is composed.

  (K) In the method of (j), wherein the compound of formula I is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, and HIV maturation inhibition Administered in combination with at least one effective amount of another HIV antiviral agent selected from the group consisting of agents.

  (L) The method of (k), wherein the at least one other HIV antiviral agent is selected from the group consisting of an HIV reverse transcriptase inhibitor and an HIV integrase inhibitor.

  (M) a procedure for administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in a method for delaying the onset or progression of AIDS in a subject in need thereof; What is composed.

  (N) The method of (m), wherein the compound is an HIV protease inhibitor, HIV reverse transcriptase inhibitor, HIV integrase inhibitor, HIV fusion inhibitor, HIV entry inhibitor, and HIV maturation inhibitor. One administered in combination with at least one effective amount of another HIV antiviral agent selected from the group consisting of.

  (O) The method of (n), wherein the at least one other HIV antiviral agent is selected from the group consisting of an HIV reverse transcriptase inhibitor and an HIV integrase inhibitor.

  (P) a method for inhibiting HIV protease in a subject in need thereof, wherein the subject is given a pharmaceutical composition of (a), (b), (c) or (d), or (e) or (f ) Comprising a procedure for administering a combination.

  (Q) In a subject in need thereof, in a method for preventing or treating HIV (eg, HIV-1), the subject is (a), (b), (c), (d) or (e ) Of the pharmaceutical composition.

  (R) In a subject in need thereof, in a method for preventing, treating or delaying the onset or progression of AIDS, subject (a), (b), (c), (d) or (e) Consisting of a procedure for administering the pharmaceutical composition.

  The invention includes (a) treatment (eg, treatment of the human body), (b) pharmaceutical, (c) inhibition of HIV protease, (d) treatment or prevention of HIV infection, or (e) treatment of AIDS, (I) for use for purposes such as prevention, or delaying its onset or progression, (ii) for use as a drug for those purposes, or (iii) in the manufacture / preparation of a drug for those purposes Also included are compounds of formula I, or pharmaceutically acceptable salts thereof, for use. In these applications, the compounds of the present invention can optionally be employed in combination with one or more other anti-HIV drugs selected from HIV antiviral drugs, anti-infective drugs, and immunomodulators.

  Additional embodiments of the present invention include pharmaceutical compositions, combinations and methods described in (a) to (r) above, and uses (i) (a)-(e) to (iii) described in the previous section. ) (A)-(e), wherein the compound of the invention employed therein is one of the embodiments, aspects, classes or subclasses described above. In all these embodiments, etc., the compound can optionally be used in the form of a pharmaceutically acceptable salt.

  Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses described in the previous section, wherein the compound of the present invention or a salt employed therein is substantially pure. is there. For a pharmaceutical composition comprised of a compound of formula I or a pharmaceutically acceptable carrier and optionally one or more excipients, the term “substantially pure” is itself a compound of formula I or its Related to salt.

As used herein, the term “alkyl” means a monovalent straight or branched saturated aliphatic hydrocarbon radical having many carbon atoms in a specific range. Thus, for example, “C _1-6 alkyl” (or “C ₁ -C ₆ alkyl”) includes any hexylalkyl and pentylalkyl isomers as well as n-, iso-, sec- and t-butyl. , N- and iso-propyl, ethyl and methyl. As another example, “C _1-4 alkyl” means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, “C _1-3 alkyl” means n-propyl, isopropyl, ethyl and methyl.

The term “alkylene” means any divalent straight or branched aliphatic hydrocarbon radical having a number of carbon atoms in a specified range. Thus, for example, “—C _1-6 alkylene-” means any C ₁ to C ₆ linear or branched alkylene, and “—C _1-4 alkylene-” means C ₁ It means any alkylene of straight or branched chain C ₄ from. A class of alkylene of interest in connection with the present invention is — (CH ₂ ) _1-6 —, and subclasses of particular interest include — (CH ₂ ) _1-4 —, — (CH ₂ ) _{2 -4} -,-(CH ₂ ) _1-3 -,-(CH ₂ ) _2-3 -,-(CH ₂ ) _1-2- , and -CH ₂ -are included. Another subclass of interest is alkylene selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, and —C (CH ₃ ) ₂ —.

The term “cycloalkyl” means any monocyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, “C _3-6 cycloalkyl” (or “C ₃ -C ₆ cycloalkyl”) means cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and “C _3-5 cycloalkyl” means Means cyclopropyl, cyclobutyl, and cyclopentyl.

  The term “halogen” (or “halo”) means fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

The term “haloalkyl” means an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced with a halogen (ie, F, Cl, Br and / or I). Thus, for example, “C _1-6 haloalkyl” (or “C ₁ -C ₆ haloalkyl”) is a C ₁ to C ₆ straight or branched chain having one or more halogen substituents as defined above. Chain alkyl group. The term “fluoroalkyl” has an analogous meaning except that the halogen substituent is limited to fluoro. Suitable fluoroalkyl include series (CH ₂ ) _0-4 CF ₃ (ie, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). included. Particular interest fluoroalkyl is CF _3.

The term “C (O)” means carbonyl. The terms “S (O) ₂ ” and “SO ₂ ” each mean sulfonyl. The term “S (O)” means sulfinyl.

  An asterisk ("*") as the end of an open bond of a chemical group means the point of attachment of that group to other parts of the compound.

  The term “aryl” means phenyl and naphthyl. An aryl of particular interest is phenyl.

  The term “heteroaryl” refers to (i) a 5 or 6 membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from N, O and S, or (ii) quinolinyl, isoquinolinyl And a heterobicyclic ring selected from quinoxalinyl. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl are included. Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.

  Examples of 4 to 7 membered saturated heterocycles within the scope of the invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, There are piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiadinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4- to 7-membered unsaturated heterocycles (see HetB) within the scope of the invention include monounsaturated heterocycles corresponding to the saturated heterocycles listed in the previous sentence. The bond is replaced with a double bond (eg, a carbon-carbon single bond is replaced with a carbon-carbon double bond).

  It is understood that the rings that can be used in the present invention are not limited to the specific rings listed above. These rings are merely representative.

  Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be incorporated into other parts of the compound, provided that a stable compound results. Can be attached at any ring atom (ie, any carbon atom or any heteroatom).

  Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing “1 to 4 heteroatoms” means that the heterocycle can contain 1, 2, 3 or 4 heteroatoms. It is also understood that any range cited herein includes all subranges within that range. Thus, for example, a heterocyclic ring described as containing "1 to 4 heteroatoms" includes, as a mode, 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 A heterocycle containing 2 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms Is intended. As another example, an aryl or heteroaryl described as optionally substituted with “1 to 4 substituents” includes, as such, 1 to 4 substituents, 2 to 4 substituents 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents And aryl or heteroaryl substituted with one substituent.

When any variable (eg, X ^A or X ^B ) is present in any component or formula I, or any other formula depicting or describing a compound of the invention, its definition for each occurrence is The definition of each other is independent. In addition, combinations of substituents and variables are allowed only when such a combination produces a stable compound.

  Unless explicitly stated to the contrary, substitution by a named substituent is permissible at any atom in the ring, as long as such ring substitution is chemically acceptable and results in a stable compound. (Eg, cycloalkyl, aryl, or heteroaryl).

  The compounds of the present invention contain asymmetric centers and, as a result of selection of substituents and substituent patterns, may contain additional asymmetric centers, and therefore, as a mixture of stereoisomers, Or they can exist as individual diastereomers or enantiomers. All isomeric forms of these compounds, either individually or as a mixture, are within the scope of the invention.

  To the extent that substituents and substituent patterns define the presence of tautomers (eg, keto-enol tautomers) within the compounds of the invention, all tautomeric forms of these compounds are individually Whether present as a mixture or as a mixture, is within the scope of the present invention. Compounds of the present invention having a hydroxy substituent on a carbon atom of the heteroaromatic ring include compounds in which only hydroxy is present, compounds in which only the tautomeric keto form (ie, oxo substituent) is present, and keto It is understood that compounds in which both the enol and enol forms exist are included.

  A “stable” compound can be prepared and isolated, and remains intact with essentially no change in structure and properties for a period of time sufficient to permit use of the compound for the purposes described herein. A compound that remains or can be left intact (eg, administration to a subject for treatment or prophylaxis). The compounds of the present invention are limited to the stable compounds encompassed by Formula I.

  The methods of the invention include inhibition of HIV protease (eg, wild type HIV-1 and / or mutant strains thereof), prevention or treatment of AIDS virus (HIV) infection, and consequent pathological conditions such as AIDS. The use of the compounds of the present invention in the prevention, treatment or delay of its onset or progression is involved. AIDS prevention, treatment of AIDS, delaying the onset or progression of AIDS, or treatment or prevention of HIV infection includes, but is not limited to, AIDS, ARC (AIDS related syndrome), both symptomatic and asymptomatic, and indeed Defined as including treatment of a wide range of conditions of HIV infection, such as exposure to top or potential HIV. For example, the present invention relates to HIV infection after suspicion of exposure to HIV has occurred by means such as blood transfusion, fluid exchange, bites, accidental needle sticks, or exposure to patient blood during surgery. Can be used to treat

  The compounds can be administered in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” has the effectiveness of the parent compound and is not biologically or otherwise undesirable (eg, toxic to its receptor, but otherwise harmful) But not) means salt. Suitable salts include, for example, acid addition salts that can be formed by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, or benzoic acid. When a compound employed in the present invention has an acidic moiety (eg, —COOH or a phenol group), suitable pharmaceutically acceptable salts thereof include alkali metal salts (eg, sodium or potassium salts), alkaline earths Also included may be salts formed with suitable organic ligands, such as metal salts (eg, calcium or magnesium salts) and quaternary ammonium salts.

  The term “administration” in relation to a compound of formula I and variations thereof (eg, “administration” of a compound) means providing the compound to an individual in need of treatment or prevention. When provided in combination with one or more other active agents (eg, antiviral agents useful in the treatment or prevention of HIV infection or AIDS), “administration” and variations thereof are compounds at the same time or at different times, respectively. And other drug supplies are understood to include. When a combination of agents is administered at the same time, they can be administered together as a single composition or administered separately.

  As used herein, the term “composition” refers to a product composed of a particular amount of a particular component, as well as any that can be obtained directly or indirectly by combining a particular component in a specified amount. It is intended to include

  “Pharmaceutically acceptable” means that the components of the pharmaceutical composition must be compatible with each other and not deleterious to the receptor.

  The term “subject” as used herein means an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experiment.

  The term “effective amount” as used herein refers to a biological or medicinal response in a tissue, strain, animal or human that is being pursued by a researcher, veterinarian, physician or other clinician. Means the amount of active compound or pharmaceutical agent to induce. In one embodiment, an effective amount is a “therapeutically effective amount” to reduce the symptoms of the disease or condition being treated. In another embodiment, an effective amount is a “prophylactically effective amount” to prevent symptoms of the disease or condition being prevented. This term includes herein the amount of active compound sufficient to inhibit HIV protease (wild type and / or mutant strains thereof) and thereby elicit the response to be pursued (ie, an “inhibitory effective amount”). ) Is also included. When an active compound (ie, active ingredient) is administered as a salt, a reference to the amount of active ingredient is to the free form (ie, non-salt form) of the compound.

In the methods of the invention (ie inhibition of HIV protease, treatment or prevention of HIV infection, or treatment, prevention of AIDS, or delaying the onset or progression of AIDS), the compound of formula I is optionally in salt form, Administration can be by any means that brings the active agent into contact with the site of action of the agent. The compounds may be administered by any conventional means that can be used with pharmaceuticals, either as individual therapeutic agents or in combination with therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the present invention can be administered in effective amounts of compounds and conventional, for example, orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally. Can be administered in a unit dosage form of a pharmaceutical composition comprising an acceptable non-toxic pharmaceutical acceptable carrier, adjuvant and vehicle. Liquid formulations suitable for oral administration (eg, suspensions, syrups, magic bullets and the like) can be prepared by techniques known in the art, and include water, glycols, oils, alcohols and the like, Any of the usual media can be employed. Solid dosage forms suitable for oral administration (eg, powders, pills, capsules and tablets) can be prepared by techniques known in the art, and also include starches, sugars, kaolins, lubricants, binders, disintegrants and the like Solid excipients such as can be employed. Parenteral compositions can be prepared by techniques known in the art, and generally employ sterile water as a carrier and optionally other ingredients to aid dissolution. Injectable solutions can be prepared according to methods known in the art, wherein the carrier is comprised of a saline solution, a glucose solution or a solution comprising a saline solution and a mixture of glucose. Further, description of suitable components for use in the appropriate way, and the composition for use in the preparation of a pharmaceutical composition for use in the present invention, ^{"Remington's Pharmaceutical Sciences, 18 th edition} , edited by A. R. Gennaro, Mack Publishing Co., 1990 ”and“ Remington-The Science and Practice of Pharmacy , 21st edition, Lippincott Williams & Wilkins, 2005 ”.

  The compound of formula I can be administered orally in single or divided doses ranging from 0.001 to 1000 mg / kg of mammalian (eg, human) body weight per day. A preferred dosage range is 0.01 to 500 mg / kg body weight per day, orally in single or divided doses. Another preferred dosage range is 0.1 to 100 mg / kg body weight per day orally in single or divided doses. For oral administration, the composition may be used for symptomatic adjustment of dosing to the patient being treated, especially 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300. , 400, 500 milligrams of active ingredient, etc., and may be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of active ingredient. The particular dose level and frequency of medication for any particular patient will vary and the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, weight, general health, gender, Depends on a variety of factors including diet, form and time of administration, excretion rate, combination drug, severity of a particular condition, and subject being treated.

  As mentioned above, the present invention may also indicate the combination of a compound of formula I with one or more anti-HIV agents. An “anti-HIV drug” is an inhibition of HIV reverse transcriptase, protease, or other enzyme required for HIV replication or infection, treatment or prevention of HIV infection, and / or treatment, prevention or onset or progression of AIDS. Any drug that is directly or indirectly effective against delay. It is understood that anti-HIV drugs are effective in treating, preventing or delaying the onset or progression of an HIV infection or AIDS and / or a disease or condition caused by or associated with it. For example, the compounds of the present invention are useful for the treatment of HIV infection or AIDS, such as those disclosed in Table 1 of WO01 / 38332 or the table of WO02 / 30930, during pre-exposure and / or post-exposure periods. An effective amount of one or more anti-HIV drug combinations can be effectively administered, selected from drugs, immunomodulators, anti-infectives, or vaccines. Suitable HIV antiviral agents for use in the combination of compounds of the present invention include, for example, those listed in Table A below.

The range of combinations of compounds of the present invention with anti-HIV drugs includes the HIV antiviral drugs listed in Table A and / or the HIV antiviral drugs listed in the tables referenced above in WO01 / 38332 and WO02 / 30930. It is understood that, in principle, any combination with any pharmaceutical composition useful for the treatment or prevention of AIDS is included. HIV antiviral drugs and other drugs are commonly employed in combination with their conventional dosage ranges and methods, as reported in the art, including, for example, “ Physicians' Desk Reference (Prescription Drug Information). Encyclopedia) , Thomson PDR, Thomson PDR, 57 ^th edition (2003), “58 ^th edition (2004)”, or “59 ^th edition (2005)”. The dosage ranges of the compounds of the invention in these combinations are the same as those described above.

  The compounds of the invention are also useful for preparing antiviral compounds and conducting screening tests. For example, the compounds of the present invention are useful for the isolation of enzyme mutants, which are excellent screening tools for more potent antiviral compounds. Moreover, the compounds of the invention are useful for establishing or determining the binding site of other antiviral drugs to HIV protease, eg, by competitive inhibition. Thus, the compounds of the present invention are commercial products sold for these purposes.

Abbreviations used in this document include: Bn = benzyl, BOC (or Boc) = t-butyloxycarbonyl, Boc ₂ O = di-t-butyl carbon salt, BOP = benzotriazol-1-yloxytris- (dimethylamino) phosphonium, BSA = bovine serum albumin CBS = Corey, Bakshi, Shibata chiral oxazaborolidine mediated ketone reduction, Cbz = benzyloxycarbonyl, DBU = 1,8-diazabicyclo [5.4.0] undec-7-one, DCAD = di -(4-Chlorobenzyl) azodicarboxylate, DCE = 1,2-dichloroethane, DCM = dichloromethane, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, Dibal-H = diisobutylaluminum hydride, DMAP 4-dimethylaminopyridine, DMF = dimethylformamide, DMSO = dimethylsulfoxide, EDC = 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, Et = ethyl, EtOAc = ethyl acetate, EtOH = ethanol, G-2G = Grubbs catalyst, 2nd generation, HOAt = 1-hydroxy-7-azabenzotriazole, HPLC = high performance liquid chromatography, HSU = hydroxysuccinimide, i-PrOH = isopropanol, LAH = lithium aluminum hydride, LC-MS = liquid chromatography Graphography-mass spectrometry, Me = methyl, MeOH = methanol, MOC = methoxycarbonyl, Ms = mesyl or methanesulfonyl, NMR = nuclear magnetic resonance, Ph = phenyl, RCM = ring-closing metathesis, Piv = Piva Royl, PPTS = pyridinium p-toluenesulfonate, PyBrOP = bromo-tris-pyrrolidinohexafluorophosphonate, SCX = strong cation exchange resin, STP = standard temperature and pressure (ie 25 ° C. and 1 atmosphere) ), TBS = tert-butyldimethylsilyl, TBDPS = tert-butyl (diphenyl) silyl, TBDPSCl = tert-butyl (dimethyl) silyl chloride, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TLC = thin layer chromatography, TMAF = tetramethylammonium fluoride (fluoride), TMSCHN ₂ = trimethylsilyl diazomethane, TPAP = tetrapropylammonium perruthenate, TPP = triphenyl Sufin.

The compounds of the present invention can be readily prepared using readily available starting materials, reagents and conventional synthetic procedures according to the following reaction schemes and examples, or variations thereof. In these reactions, it is also possible to use variants that are known per se to the person skilled in the art but are not mentioned in more detail. Moreover, other methods for preparing the compounds of the present invention will be readily apparent to those skilled in the art in light of the reaction schemes and examples below. Unless otherwise indicated, all variables are as previously defined. The term "Ar" is appearing in some of Scheme but means phenyl optionally substituted with one or more X ^A.

  Scheme A depicts the synthesis of an alkylated lysine amine compound of the invention, wherein the carbamate protected amine A1 can be sulfonylated by reaction with a suitable arylsulfonyl halide to give A2. This can then be alkylated with TPP and azodicarboxylate with the appropriate substituted alcohol to give A3. Intermediate A3 can be deprotected by treatment with hydrogen in the presence of a palladium catalyst to give amine A4, which is then appropriately purified by conventional amidation methods such as treatment with BOP. By conjugation with a substituted amino acid, amide A5 can be obtained. The ester group of A5 can be saponified with a hydroxyl base (eg, NaOH or KOH) to give carboxylic acid A6, which can then be converted to amide A7 using an amide bond forming reagent such as BOP. The amide functional group at A7 can then be reduced (eg, treated with a borane reducing agent) to provide the desired compound A8.

  Scheme A ′ depicts a method for synthesizing the alkylated ricinol compounds of the present invention, wherein the ester group of intermediate A5 is reduced (eg, treated with a metal hydride such as lithium borohydride). The desired alcohol A9 can be obtained.

Scheme A ″ depicts the method of synthesizing the secondary ricinol or lysine carbyne amines of the present invention, where a compound of type A9 is an amine (R ⁷ = carbamate, carbonyl, sulfonyl Etc.) for the aldehyde A10 with the appropriate R ⁷ group. In a suitable oxidation method, sulfur trioxide-pyridine complex is used in the method described in “Parikh & Doering, J. Am. Chem. Soc 1967, 89 : 5505”. A10 can be treated with an organometallic-derived nucleophile such as magnesium methyl bromide or methyllithium to give the desired compound A11.

Also depicted in Scheme A ″ is the reaction of aldehyde intermediate A10 with Ellman sulfinamide to obtain the corresponding sulfinamine derivative (Ellman et al, J. Am. Chem. Soc, 1967, 120, 8011-8012), which is then treated with an organometallic nucleophile (identified as R ^J -M in the scheme) and then with acid to remove the chiral auxiliary, Compound A12 can be obtained.

Scheme B depicts another synthesis of the alkyl-substituted ricinol compounds of the present invention, where an appropriately substituted olefinic amino acid B1 is protected with Boc anhydride and an amide bond such as an EDC or BOP reagent. The forming reagent and a suitable amine such as unsubstituted or substituted allylamine can be used to convert to amide B2. The Boc protecting group can be removed under acidic conditions and the resulting amine can be a tertiary amine (eg, TEA), hydroxide (eg, NaOH), or carbon salt (eg, sodium bicarbonate), etc. Can be sulfonylated with a suitable arylsulfonyl halide in the presence of a base scavenger to yield B3. B3 sulfonylamino nitrogen is an alkyl alcohol containing ^{R Q,} is reacted under standard Mitsunobu conditions can alkylated and then B3 _is treated with Boc 2 O / DMAP, to obtain the B4 Yes (see “Brass et al., Tetrahedron 2006, 1777”). Diene B4 can be converted to lactam B5 using standard reagents that influence the ring-closing metathesis reaction (eg, second generation Grubbs catalyst). Lactam B5 can be reduced (eg, a borohydride reagent in an alcoholic solvent) to yield B6, followed by hydrogenation and deprotection under acidic conditions (eg, HCl) to yield an amino alcohol B7 can be obtained. The amino group of B7 can then be coupled with an appropriately substituted amino acid to give the desired amide B8.

Scheme C depicts another synthesis of the alkylated ricinol compounds of the present invention, wherein an appropriately substituted olefinic amino acid C1 is conjugated with a tertiary amine (using an appropriate arylsulfonyl halide). For example, C2 can be obtained by sulfonylation in the presence of a base scavenger such as TEA), hydroxide (eg, NaOH), or carbon salt (eg, sodium bicarbonate). Sulfonamide C2 can be alkylated with the appropriate alcohol using Mitsunobu conditions in the presence of TPP and azodicarboxylate, and then saponified with a hydroxyl base such as NaOH or KOH to give intermediate C4. it can. Compound C4 can be coupled to an olefin amine using an amide bond forming reagent such as BOP to give amide C5. C5 dienes can be converted to lactam C6 using standard reagents that affect ring-closing metathesis reactions such as second generation Grubbs catalysts. The lactam protecting group is removed by exposing C6 to strongly acidic conditions, and then the double bond is removed by standard hydrogenation conditions (eg, carbon-supported Pd or carbon-supported Pd (OH) ₂ ) and hydrogen gas. It can be used and reduced to give C7. The lactam C7 is then treated with Boc anhydride, subjecting the Boc protected lactam to reductive ring opening and reacting with a borohydride reagent in an alcoholic solvent such as methanol or ethanol to yield C8. be able to. After deprotection of C8 by treatment with an acid such as TFA, the desired compound C9 can be obtained by conjugation with an appropriately substituted amino acid derivative.

Scheme D depicts another synthesis of the alkylated ricinol compounds of the present invention, where a suitably protected glutamic acid derivative such as D1 is esterified and Boc protected to fully protected glutamate Derivative D2 can be obtained. Glutamate derivative D2 can be selectively reduced using an appropriate reducing agent to give aldehyde D3, which is treated with an appropriately substituted nitroalkyl group and a catalytic base such as tetramethylguanidine. Thus, a Henry reaction (see, for example, “Comp. Org. Syn. 1991, 2 : 321”) can occur. The resulting Henry adduct can be validated with a reagent such as mesyl chloride and then treated with an amine base such as TEA to yield D4. The double bond of D4 can be reduced by hydrogenation in the presence of a Pd source to give amino acid D5, which is treated with an amino protecting agent such as Cbz chloride and then with alcoholic HCl. By treatment, D6 can be obtained by continuous protection and deprotection. D6 can be sulfonylated with an appropriate arylsulfonyl halide in the presence of a base to give D7, which is then used with TPP and azodicarboxylate under Mitsunobu alkylation conditions with an appropriately substituted alcohol. Can be alkylated to obtain D8. Intermediate D8 can then be deprotected using hydrogen and palladium catalysts to give the amine, which can be coupled with an appropriately substituted amino acid derivative to give D9, which in turn is To obtain the desired D10. Chiral separation can yield all stereoisomers that can be identified by enzymatic inhibition evaluation. The absolute assignment of stereochemistry at R ₅ with an epsilon center can be obtained by co-crystallization with HIV protease.

Alternatively, amine D5 can be coupled directly to an appropriately substituted amino acid derivative after concomitant Boc removal and esterification to give intermediate D11. Sulfonylation with an appropriate arylsulfonyl halide in the presence of a base provides sulfonamide D12, at which point diastereoisomers at R ₅ with an epsilon center can be separated by flash chromatography. The desired isomer (R ₅ with α as shown in D12) can be obtained from both diastereoisomers using Mitsunobu alkylation, nitro and ester reduction as described above, and enzymatic inhibition evaluation for both diastereoisomers. The body can be identified by converting it to the final compound D13. The absolute assignment of stereochemistry at R ₅ with an epsilon center can be obtained by co-crystallization with HIV protease.

Scheme E depicts the first method used to introduce R ⁵ substituents that can control diastereoselectivity. Boc lysine E1 is converted to the corresponding bis-Boc intermediate on which the ester is reduced, resulting in alcohol protection as a silyl ether, yielding intermediate E2. After selective RuO ₄ mediated oxidation (α to terminal NHBoc) according to “Tetrahedron Lett. 1998, 39 , 5671”, the resulting reduction of the imide gives alcohol E3. Protecting the terminal hydroxyl group as pivalate or benzyl ether allows subsequent alkylation of the NHBoc group at R ¹ including halide, yielding intermediate E4. After removal of pivalate or benzyl ether, the resulting primary alcohol is oxidized to the corresponding aldehyde and converted to the corresponding diastereomerically pure optimal Ellman sulfinimide. E5 is obtained. Diastereoselective introduction of the R ⁵ group can be achieved by adding R ⁵ containing Grignard reagent to the functionality of Ellman sulfinimide. Treatment with a controlled amount of HCl in MeOH provides the amino-alcohol E6. Following conjugation of an appropriately substituted amino acid derivative, Boc removal and sulfonylation provides the desired type of compound E7. Reduction of the nitro or ester functionality on the Ar group can also be performed at this stage if desired.

Scheme F depicts the use of a cross-metathesis method to introduce a substituted lysine side chain and the use of diastereoselective reduction of Ellman sulfinimide to control stereochemistry at the centered R ^5. . Allyl glycine is converted to the corresponding methyl or ethyl ester, followed by sulfonylation and alkylation under Mitsunobu conditions to give intermediate F2. By cross metathesis using Grubbs second generation catalyst with R ⁵ with crotyl ketone (see “Handbook of Metathesis; Grubbs, RH, Ed .; Wiley-VCH: Weinheim, 2003”) After hydrogenation of the nitro group, ketone F3 is obtained. After conversion to the corresponding diastereoisomerically pure optimal Ellman sulfinimide, diastereoselective reduction and removal of the Ellman group under acidic conditions gives the amine F4. Conjugation of appropriately substituted amino acid derivatives and reduction of the ester group yields the desired type of product F5.

Scheme G depicts a variation on the method described in Scheme F, which later permits the introduction of arylsulfonamido groups and R ¹ groups. Allylglycine is converted to the Boc ester derivative G2, which is then converted to ketone G3 and then to amine G4 by olefin cross-metathesis in a manner similar to that described above in Scheme F. Conjugation of appropriately substituted amino acid derivatives and removal of Boc yields intermediate G5 ready for sulfonylation and Mitsunobu alkylation, and ultimately, after ester reduction, the desired type of compound G6.

Scheme H depicts a variation on the method described in Scheme G, which allows the introduction of a CF ₃ or CF ₂ -alkyl group at the R ⁵ position. Aldehyde H2 is prepared using the method described in Schemes F and G, after which Ellman sulfinimide is prepared as described above, and then treated with CF ₃ -TMS and fluoride sources to produce CF ₃ groups. The diastereoselective anti-addition of can be obtained, whereby amine H3 can be obtained after HCl / MeOH treatment. Following conjugation of an appropriately substituted amino acid derivative, Mitsunobu alkylation, nitro and ester reduction yields the desired type of compound H4.

Scheme I depicts another approach for the preparation of ketone type I2. Cyclic imide I1 can be converted to its corresponding ester-Boc-imide, which can then be regioselectively opened by addition of R ⁵ containing Grignard to give ketone I2. Conversion of ketone I2 to the desired type of product I5 proceeds as previously described in Scheme G.

In Part 1 of Scheme J, another method for obtaining an aldehyde intermediate as a precursor to Ellman sulfinimide is depicted. Amino acid J1 (commercially available) is converted to benzyl ether J2 by esterification, sulfonylation and Mitsunobu alkylation. Simultaneous reduction of both methyl esters and consequent protection of the alcohols as silyl ethers allows selective hydrogenolysis of the terminal benzyl ether, which is then oxidized to the corresponding aldehyde J3. It becomes. At this point, Ellman sulfinimide is prepared and treated with either R ⁵ containing Grignard or CF ₃ -TMS and a fluoride source to permit the introduction of a diastereoselective R ₅ group. Deprotection of the sulfimin group and silyl ether under acidic conditions and conjugation of an appropriately substituted amino acid derivative provides the desired type of product J4. Part 2 of Scheme J, a variation of Part 1, describes the preparation of a branched benzyl alcohol derivative of type J7. The preparation of acetophenone of type J5 is carried out using a method similar to that just described for the conversion of J1 to J2. The acetophenone group should be diastereoselectively reduced using the Corey CBS method (“J. Am. Chem. Soc. 1987, 109 , 5551-5553 and 7925-7926”) and protected with the corresponding silyl ether. Can do. At this point, the ester is reduced and protected as the corresponding silyl ether, and then the terminal alcohol is deprotected and oxidized to the aldehyde intermediate J6. The conversion of the desired type of product J7 follows the same method as just described for the J3 to J4 conversion.

  Scheme K depicts the combination of methods used in F and J. Allyl glycine is converted into bisester K2, which can be reduced and protected as bissilyl ether K3. After olefin cross-metathesis with crotonaldehyde ("Handbook of Metathesis, Grubbs, R.H., Ed., Wiley-VCH: Weinheim, 2003"), double-bond hydrogenation yields an aldehyde of type K4, This can then be converted to the desired type of product K5 following a process similar to that described in Scheme J. As described in Scheme J, small-scale changes allow the conversion of K1 to type K9 branched benzyl alcohols. Selective benzylic oxidation provides acetophenone of type K10.

Scheme L depicts the preparation of a spiroepsilon substituted compound of type L4 and a gem 2 substituted compound of type L9. Part 1 depicts spiro compounds, where after Michael addition of a nitro derivative of type L1 to acrolein (Org. Lett. 2003, 5 (17), 3155-3158), Horner Emmons addition gives an intermediate of type L2. Subsequent nitro reduction and Cbz removal followed by sulfonylation provides an intermediate of type L3. Conjugation of appropriately substituted amino acid derivatives, introduction of the R ¹ group, nitro and ester reduction yields the desired type of product L4. Part 2 describes the preparation of the desired type of product L9 from it in a manner similar to Part 1 for the preparation of the gem 2 substituted intermediate of type L7.

Scheme M depicts the preparation of a hydroxymethyl derivative of type M3.
2,6-Diaminoheptanedioic acid can be converted to a bisester and then monosulfonylated, followed by Cbz introduction to give intermediate M2. After the introduction of R ¹ , derivatives of type M3 are obtained by conjugation of appropriately substituted amino acid derivatives and reduction of the ester group.

In compounds of formula I wherein R ² is CH (R ^J ) —OR ^P , the R ^P group is a method described in WO 2006/012725 (eg, Scheme 1, 1A, 2, 3, 4 and WO ′ 725 5)) or similar or identical procedure.

  The following examples serve only to illustrate the invention and its method of implementation. The examples should not be construed as limiting the scope or spirit of the invention.

  The term “room temperature” in the examples refers to an ambient temperature generally in the range of about 19 ° C. to 26 ° C.

Preparation Example Intermediate 1: N- (2,4-Dimethoxybenzyl) -2-methylprop-2-en-1-amine

１００ｍＬのＤＣＭ中に、５．５５ｇ（２７．３ｍｍｏｌ）の２，４−ジメトキシベンジルアミン塩酸塩および３．６８ｇ（２７．３ｍｍｏｌ）のプロペニル臭化物を含む溶液に、８．０ｍＬ（５７．２ｍｍｏｌ）のＴＥＡを加えた。反応混合物を１６時間攪拌し、５０ｍＬのＮａＨＣＯ_３溶液で希釈し、ＤＣＭ（３ｘ）で洗浄した。有機抽出物を乾燥、濃縮し、残留物をクロマトグラフィーで分離（（９５／５／０．５）ＤＣＭ／ＭｅＯＨ／ＮＨ_４ＯＨ）して、望ましいアミンが得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝２２２．５。

To a solution containing 5.55 g (27.3 mmol) 2,4-dimethoxybenzylamine hydrochloride and 3.68 g (27.3 mmol) propenyl bromide in 100 mL DCM, 8.0 mL (57.2 mmol) TEA was added. The reaction mixture was stirred for 16 h, diluted with 50 mL of NaHCO ₃ solution and washed with DCM (3 ×). The organic extract was dried and concentrated and the residue was chromatographed ((95/5 / 0.5) DCM / MeOH / NH ₄ OH) to give the desired amine. LCMS [M + H] ⁺ = 222.5.

Example A1
(2S) -2-amino-N- {5-[[(4-aminophenyl) sulfonyl]-(3-methylbutyl) amino] -6-hydroxyheptyl} -3,3-diphenylpropanamide

手順Ａ１−１：ｔｅｒｔ−ブチル［（１Ｓ）−２−（｛５−［［（４−アミノフェニル）スルホニル］（３−メチルブチル）アミノ］−６−ヒドロキシヘプチル｝アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩

Procedure A1-1: tert-butyl [(1S) -2-({5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxyheptyl} amino) -1- (diphenylmethyl ) -2-Oxoethyl] carbamate

「Ｓｔｒａｎｉｘ ｅｔ ａｌ．Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．２００６，１６（１３）：３４５９」で説明されているとおりに調製したｔｅｒｔ−ブチル［（１Ｓ）−２−（｛（５Ｓ）−５−［［４−アミノフェニル）スルホニル］（３−メチルブチル）アミノ−６−ヒドロキシヘキシル）アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩（５００ｍｇ、０．７３４ｍｍｏｌ）およびヒューニッヒ塩基（０．６４１ｍＬ、３．６７ｍｍｏｌ）を、５ｍＬのＤＭＳＯおよび２．６ｍＬのＣＨ_２Ｃｌ_２に入れた溶液に、−１０℃で、ＳＯ_３−Ｐｙ（５８４ｍｇ、３．６７ｍｍｏｌ）を２．８ｍＬのＤＭＳＯに入れたものをカニューレで加えた。槽を除去し、反応を室温で３時間進行させた。反応混合物を２Ｍ Ｎａ_２Ｓ_２Ｏ_３を加えて急冷し、室温で３０分間激しく攪拌した。反応混合物をＥｔＯＡｃで希釈し、層を分離し、有機物を２Ｍ Ｎａ_２Ｓ_２Ｏ_３（１×）、３Ｍ ＬｉＣｌ（３×）およびブラインで洗浄した。有機物をＮａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（０−＞１５％ＭｅＯＨ／ＣＨ_２Ｃｌ_２、線形勾配）により精製し、望ましい生成物が白色の固体として得られた。
ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６７９。

Tert-Butyl [(1S) -2-({(5S) -5- [] prepared as described in “Stranix et al. Bioorg. Med. Chem. Lett. 2006, 16 (13): 3459”. [4-Aminophenyl) sulfonyl] (3-methylbutyl) amino-6-hydroxyhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate (500 mg, 0.734 mmol) and Hunig base (0. 641 mL, 3.67 mmol) in a solution of 5 mL of DMSO and 2.6 mL of CH ₂ Cl ₂ at −10 ° C. with SO ₃ -Py (584 mg, 3.67 mmol) in 2.8 mL of DMSO. Was added with a cannula. The tank was removed and the reaction was allowed to proceed for 3 hours at room temperature. The reaction mixture was quenched with the addition of 2M Na ₂ S ₂ O ₃ and stirred vigorously at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc, the layers were separated, and the organics were washed with 2M Na ₂ S ₂ O ₃ (1 ×), 3M LiCl (3 ×) and brine. The organics were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (0-> 15% MeOH / CH ₂ Cl ₂ , linear gradient) to give the desired product as a white solid.
LCMS [M + H] ⁺ = 679.

Procedure A1-2: tert-butyl [(1S) -2-({5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxyheptyl} amino) -1- (diphenylmethyl ) -2-Oxoethyl] carbamate

手順Ａ１−１からのアルデヒド（１００ｍｇ、０．１４７ｍｍｏｌ）を２．９ｍＬ ＴＨＦに入れた溶液に、−７８℃でＭｅＭｇＢｒ（Ｅｔ_２Ｏ中の３Ｍ溶液として０．４９ｍＬ、１．４７ｍＬ）を加えた。反応混合物を２時間にわたり−１５℃まで温め、飽和ＮＨ_４Ｃｌ、ＥｔＯＡｃの順に加えて反応混合物を急冷した。層を分離し、有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（０−＞１５％ＭｅＯＨ／ＣＨ_２Ｃｌ_２、線形勾配）により精製し、^１Ｈ ＮＭＲによる１：１のジアステレオマー混合物である望ましい生成物が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６９５。

To a solution of the aldehyde from procedure A1-1 (100 mg, 0.147 mmol) in 2.9 mL THF was added MeMgBr (0.49 mL, 1.47 mL as a 3M solution in Et ₂ O) at −78 ° C. . The reaction mixture was warmed to −15 ° C. over 2 h and quenched with saturated NH ₄ Cl, EtOAc in that order. The layers were separated and the organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography _{(0-> 15% MeOH / CH} 2 Cl 2, linear gradient) to ^afford 1 by 1 H NMR: the desired product which is a 1 diastereomeric mixture as a white solid It was. LCMS [M + H] ⁺ = 695.

Procedure A1-3: (2S) -2-amino-N- {5-[[(4-aminophenyl) sulfonyl]-(3-methylbutyl) amino] -6-hydroxyheptyl} -3,3-diphenylpropanamide To a solution of the product from Procedure A1-2 (25 mg, 0.036 mmol) in 0.72 mL CH ₂ Cl ₂ was added 0.67 mL 4M HCl in dioxane. After 2 hours, the reaction mixture was concentrated, redissolved in 1 mL DMF, and purified by preparative HPLC (Sunfire column, 15 mL / min) to give the title compound as a 1: 1 mixture of diastereomers that could not be separated. . The ¹ H NMR data tabulated below is for this diastereomeric mixture. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.82 (m, 1H), 7.50-7.43 (m, 4H), 7.39 (t, J = 7.5 Hz, 2H), 7. 32-7.21 (m, 6H), 6.74 (dd, J = 8.6, 1.5 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 4.31 (d , J = 11.7 Hz, 1H), 3.69 (m, 1H (from one diastereomer)), 3.55 (m, 1H (from one diastereomer)), 3.44 (m, 1H (from one diastereomer), 3.33 (m, 1H (from one diastereomer)), 3.17 to 3.00 (m, 4H), 2.71 (m, 1H), 1.58 to 1.28 (m, 6H), 1.11 (d, J = 6.2 Hz, 3H (from one diastereomer)), 1 04 (d, J = 6.4Hz, 3H (from one diastereomer)), 0.92 (m, 2H), 0.85 (m, 6H). LCMS [M + H] ⁺ = 595.

Example A2
Methyl [(1S) -2-({6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -hexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] Carbamate

手順Ａ２−１：メチル（２Ｓ）−６−｛［（ベンジルオキシ）カルボニル］アミノ｝−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝ヘキサン酸塩

Procedure A2-1: Methyl (2S) -6-{[(benzyloxy) carbonyl] amino} -2-{[(4-nitrophenyl) sulfonyl] amino} hexanoate

１００ｍＬのＤＣＭ中で５．０ｇ（１７ｍｍｏｌ）のエステルを含む溶液に、４．７ｍＬ（３４ｍｍｏｌ）のトリエチルアミンを加えた後、３．７ｇ（１７ｍｍｏｌ）のｐ−塩化ニトロベンゼンスルホニルを加え、および結果として生じる混合物を室温で１６時間攪拌させた。溶液を１ Ｎ ＨＣｌ（２×２０ｍＬ）、飽和ＮａＨＣＯ_３（２×１０ｍＬ）、水（１０ｍＬ）、およびブライン（１０ｍＬ）で洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィー（３３％から５０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝４８０．１。

To a solution containing 5.0 g (17 mmol) of ester in 100 mL of DCM, 4.7 mL (34 mmol) of triethylamine is added followed by 3.7 g (17 mmol) of p-nitrobenzenesulfonyl chloride and the resulting The mixture was allowed to stir at room temperature for 16 hours. The solution was washed with 1 N HCl (2 × 20 mL), saturated NaHCO ₃ (2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over MgSO ₄ , concentrated and chromatographed (33% to 50% to 100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 480.1.

Procedure A2-2: Methyl (2S) -6-{[(benzyloxy) carbonyl] amino} -2-{(3-methylbutyl) [(4-nitrophenyl) sulfonyl] amino} hexanoate

スルホンアミドＡ２−１（１．０ｇ、２．０９ｍｍｏｌ）を１０ｍＬのＴＨＦに溶かし、トリフェニルホスフィン（６５６ｍｇ、２．５ｍｍｏｌ）、イソアミルアルコール（２２１ｍｇ、２．５ｍｍｏｌ）、およびＤＩＡＤ（５０６ｍｇ、２．５ｍｍｏｌ）で順次に処理し、結果として生じる溶液を室温で７２時間攪拌させた。反応混合物を濃縮し、クロマトグラフィー（５０％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝５５０．２。

Sulfonamide A2-1 (1.0 g, 2.09 mmol) was dissolved in 10 mL of THF and triphenylphosphine (656 mg, 2.5 mmol), isoamyl alcohol (221 mg, 2.5 mmol), and DIAD (506 mg, 2.5 mmol). ) And the resulting solution was allowed to stir at room temperature for 72 hours. The reaction mixture was concentrated and separated by chromatography (50% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 550.2.

Procedure A2-3: Methyl (2S) -6-amino-2-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] hexanoate

２．０ｇ（３．６４ｍｍｏｌ）の化合物Ａ２−２を含む脱気した溶液を、５０ｍＬのＭｅＯＨに溶かしたものを、５００ｍｇの２０％Ｐｄ（ＯＨ）_２で処理し、ＳＴＰで２時間にわたり水素化した。反応混合物をセライトを通過させて濾過し、蒸発させて、望ましい化合物を残した。ＬＣＭＳ（Ｍ＋１）＝３８６．０。

A degassed solution containing 2.0 g (3.64 mmol) of compound A2-2 dissolved in 50 mL of MeOH was treated with 500 mg of 20% Pd (OH) ₂ and hydrogenated with STP for 2 hours. did. The reaction mixture was filtered through celite and evaporated to leave the desired compound. LCMS (M + 1) = 386.0.

Procedure A2-4: Methyl 2-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylprop Noyl} amino) hexanoate

手順Ａ２−３のアミン（１．０ｇ、２．５９ｍｍｏｌ）およびＮ−Ｍｏｃ−（Ｓ）−ジフェニルアラニン（８５４ｍｇ、２．８５ｍｍｏｌ）を２０ｍＬ ＤＣＭに入れた溶液に、ジイソプロピルエチルアミン（８０５ｍｇ、６．２３ｍｍｏｌ）およびＢＯＰ試薬（１．３８ｇ、３．１１ｍｍｏｌ）を加えた。６０分後、反応混合物をＤＣＭで希釈し、飽和ＮａＨＣＯ_３で洗浄した。有機相を分離し、乾燥させ、蒸発させた。カラムクロマトグラフィー（８０％ＥｔＯＡｃ／ヘキサン）により、望ましい付加物が白色の固体として得られた。ＬＣＭＳ（Ｍ＋１）＝６６７．８。

To a solution of the procedure A2-3 amine (1.0 g, 2.59 mmol) and N-Moc- (S) -diphenylalanine (854 mg, 2.85 mmol) in 20 mL DCM was added diisopropylethylamine (805 mg, 6.23 mmol). ) And BOP reagent (1.38 g, 3.11 mmol) were added. After 60 minutes, the reaction mixture was diluted with DCM and washed with saturated NaHCO ₃ . The organic phase was separated, dried and evaporated. Column chromatography (80% EtOAc / hexanes) gave the desired adduct as a white solid. LCMS (M + 1) = 667.8.

Procedure A2-5: 2-[[(4-Aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl } Amino) hexanoic acid

６６７ｍｇ（１．００ｍｍｏｌ）のエステルを３ｍＬのＴＨＦおよび３ｍＬの水に溶かした溶液を、３ｍＬ（６．０ｍｍｏｌ）の２Ｎ ＬｉＯＨで処理し、結果として生じる混合物を室温で１６時間攪拌した。混合物を１Ｎ ＨＣｌでｐＨ＝５に酸性化し、ＥｔＯＡｃ（３×１０ｍＬ）で洗浄した。混合した有機物をＭｇＳＯ_４上で乾燥させ、濃縮させると、望ましい酸が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６５３。

A solution of 667 mg (1.00 mmol) of the ester in 3 mL of THF and 3 mL of water was treated with 3 mL (6.0 mmol) of 2N LiOH and the resulting mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N HCl to pH = 5 and washed with EtOAc (3 × 10 mL). The combined organics were dried over MgSO ₄ and concentrated to give the desired acid. LCMS [M + H] ⁺ = 653.

Procedure A2-6: Methyl [(1S) -2-({6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-oxohexyl} amino) -1- ( Diphenylmethyl) -2-oxoethyl] carbamate

上記の手順Ａ２−５からのカルボン酸（６５ｍｇ、０．１０ｍｍｏｌ）および塩化アンモニウム（１０．４ｍｇ、０．２ｍｍｏｌ）を１ｍＬ ＤＭＦに入れた溶液に、トリエチルアミン（０．０４０ｍＬ、０．２８５ｍｍｏｌ）およびＢＯＰ試薬（８８ｍｇ、０．２００ｍｍｏｌ）を加えた。３０分後、反応混合物をＥｔＯＡｃで希釈し、有機物をＨ_２Ｏおよびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物を逆相クロマトグラフィーで精製し、粘性の油である望ましい付加物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６５２．８。

To a solution of the carboxylic acid from procedure A2-5 above (65 mg, 0.10 mmol) and ammonium chloride (10.4 mg, 0.2 mmol) in 1 mL DMF was added triethylamine (0.040 mL, 0.285 mmol) and BOP. Reagent (88 mg, 0.200 mmol) was added. After 30 minutes, the reaction mixture was diluted with EtOAc and the organics were washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase chromatography to give the desired adduct, a viscous oil. LCMS [M + H] ⁺ = 652.8.

Procedure A2-7: Methyl [(1S) -2-({6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -hexyl) amino) -1- (diphenylmethyl) 2-Oxoethyl] carbamate To a solution of 50 mg (0.07 mmol) of the amide from Procedure A2-6 above in 1 mL of THF was added 0.04 mL (0.08 mmol) of 2M borane in THF. added. The resulting mixture was stirred at room temperature for 16 hours, quenched with 1 mL of MeOH and evaporated to dryness. The residue was subjected to reverse phase chromatography to give the desired amine as a white blowing agent.
¹ H NMR (CDCl ₃ ): δ 7.60 to 7.58 (d, J = 9 Hz, 2H), 7.34 to 7.19 (m, 10H), 6.72 to 6.70 (d, J = 9 Hz, 2H), 5.57 (brs, 1H), 5.23 to 5.21 (d, J = 8 Hz, 1H), 4.81 to 4.77 (m, 1H), 4.46 to 4 .39 (m, 3H), 3.74 to 3.32 (m, 6H), 3.19 to 3.11 (m, 2H), 2.90 to 2.85 (m, 1H), 2.68 To 2.56 (m, 3H), 1.57 to 0.86 (m, 13H), 0.57 (br s, 2H). LCMS [M + H] ⁺ = 638.8.

Example B1
(2S) -2-amino-N-((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) -sulfonyl] amino} hexyl) -3,3- Diphenylpropanamide

手順Ｂ１−１：（２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−４−メチルペンタン−４−エン酸

Procedure B1-1: (2S) -2-[(tert-butoxycarbonyl) amino] -4-methylpentane-4-enoic acid

（２Ｓ）−２−アミノ−４−メチル−４−ペンテン酸（５００ｍｇ、３．８７ｍｍｏｌ）を１３ｍＬのジオキサンおよび３．９ｍＬ ３Ｍ ＮａＯＨに入れた溶液に、Ｂｏｃ_２Ｏ（８８７ｍｇ、４．０６ｍｍｏｌ）を一度に加えた。反応を室温で１６時間進行させた後、１Ｎ ＨＣｌを加えてｐＨから２まで酸性化した。水相をＣＨＣｌ_３（４ｘ）で抽出し、混合した有機物をＮａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、望ましい保護アミノ酸が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝２３０。

To a solution of (2S) -2-amino-4-methyl-4-pentenoic acid (500 mg, 3.87 mmol) in 13 mL dioxane and 3.9 mL 3M NaOH was added Boc ₂ O (887 mg, 4.06 mmol). Added at once. The reaction was allowed to proceed for 16 hours at room temperature and then acidified from pH to 2 by adding 1N HCl. The aqueous phase was extracted with CHCl ₃ (4 ×) and the combined organics were dried over Na ₂ SO ₄ , filtered and concentrated to give the desired protected amino acid as a white solid. LCMS [M + H] ⁺ = 230.

Procedure B1-2: tert-butyl {(1S) -1-[(allylamino) carbonyl] -3-methylbut-3-en-1-yl} carbamate

上記の手順Ｂ１−１からのＮ−Ｂｏｃ保護アミノ酸（８９３ｍｇ、３．８９ｍｍｏｌ）を１３ｍＬ ＣＨＣｌ_３に入れた溶液に、アリルアミン（０．３５ｍＬ、４．６７ｍｍｏｌ）を加えた後、ＥＤＣ−ＨＣｌ（８９６ｍｇ、４．６７ｍｍｏｌ）およびＨＯＡｔ（５３ｍｇ、０．３８９ｍｍｏｌ）を加えた。反応を室温で１６時間進行させた後、ＥｔＯＡｃで希釈した。有機物を１Ｎ Ｈ ＨＣｌ、飽和ＮａＨＣＯ_３水溶液およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、望ましい結合した付加物が白色の固体として得られたが、これをそれ以上精製することなく使用した。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝２６９。

To a solution of N-Boc protected amino acid from Procedure B1-1 above (893 mg, 3.89 mmol) in 13 mL CHCl ₃ was added allylamine (0.35 mL, 4.67 mmol) followed by EDC-HCl (896 mg). 4.67 mmol) and HOAt (53 mg, 0.389 mmol) were added. The reaction was allowed to proceed for 16 hours at room temperature and then diluted with EtOAc. The organics were washed with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired combined adduct as a white solid. Used without further purification. LCMS [M + H] ⁺ = 269.

Procedure B1-3: (2S) -N-allyl-4-methyl-2-amino-4-methylpent-4-enamide

手順Ｂ１−２からの付加物を、１７ｍＬ ＥｔＯＡｃに溶かし、０℃まで冷ました。反応により５分間ＨＣｌガス気泡を発生させ、反応混合物を室温まで１時間温めた。反応混合物を０℃まで冷まして戻し、反応により２分間ＨＣｌガス気泡を発生させた。反応混合物を室温まで１時間温め、濃縮させて、望ましい生成物が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝１６９。

The adduct from Procedure B1-2 was dissolved in 17 mL EtOAc and cooled to 0 ° C. The reaction generated HCl gas bubbles for 5 minutes and the reaction mixture was warmed to room temperature for 1 hour. The reaction mixture was cooled back to 0 ° C. and the reaction generated HCl gas bubbles for 2 minutes. The reaction mixture was warmed to room temperature for 1 hour and concentrated to give the desired product as a white solid. LCMS [M + H] ⁺ = 169.

Procedure B1-4: (2S) -N-allyl-4-methyl-2-{[(4-methylphenyl) sulfonyl] amino} pent-4-enamide

手順Ｂ１−３からの生成物（６１０ｍｇ、２．９８ｍｍｏｌ）を１５ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、トリエチルアミン（０．８３１ｍＬ、５．９６ｍｍｏｌ）を加えた。トシル塩化物（５６８ｍｇ、２．９８ｍｍｏｌ）を一度に加え、反応を室温で３６時間進行させた。反応混合物をＥｔＯＡｃで希釈し、有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（１０−＞６５％ＥｔＯＡｃ／ヘキサン、線形勾配）を使用して精製し、望ましい生成物が粘性の油として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝３２３。

To a solution of the product from Procedure B1-3 (610 mg, 2.98 mmol) in 15 mL CH ₂ Cl ₂ was added triethylamine (0.831 mL, 5.96 mmol). Tosyl chloride (568 mg, 2.98 mmol) was added in one portion and the reaction was allowed to proceed at room temperature for 36 hours. The reaction mixture was diluted with EtOAc and the organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified using silica gel chromatography (10-> 65% EtOAc / hexanes, linear gradient) to give the desired product as a viscous oil. LCMS [M + H] ⁺ = 323.

Procedure B1-5: (2S) -N-allyl-4-methyl-2-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} pent-4-enamide

手順Ｂ１−５からの生成物（５４６ｍｇ、１．６９ｍｍｏｌ）を５．６ｍＬ ＴＨＦに入れた溶液に、３−メチルブタノール（０．２６ｍＬ、２．３７ｍｍｏｌ）、Ｐｈ_３Ｐ（６２２ｍｇ、２．３７ｍｍｏｌ）およびＤＩＡＤ（０．４６ｍＬ、２．３７ｍｍｏｌ）をその順序で加えた。反応を室温で３時間進行させた後濃縮させて、残留物をシリカゲルクロマトグラフィー（０−＞２０％ＥｔＯＡｃ／ヘキサン、線形勾配）で精製し、望ましい生成物が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝３９３。

To a solution of the product from Procedure B1-5 (546 mg, 1.69 mmol) in 5.6 mL THF, 3-methylbutanol (0.26 mL, 2.37 mmol), Ph ₃ P (622 mg, 2.37 mmol). And DIAD (0.46 mL, 2.37 mmol) were added in that order. The reaction was allowed to proceed at room temperature for 3 hours and then concentrated and the residue was purified by silica gel chromatography (0-> 20% EtOAc / hexanes, linear gradient) to give the desired product as a white solid. LCMS [M + H] ⁺ = 393.

Procedure B1-6: tert-Butylallyl ((2S) -4-methyl-2-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} pent-4-enoyl) carbamate

手順 Ｂ１−５からのアミド（１７３ｍｇ、０．４４１ｍｍｏｌ）を２．２ｍＬ ＣＨ_３ＣＮに入れた溶液に、Ｂｏｃ_２Ｏ（２８９ｍｇ、１．３２ｍｍｏｌ）およびＤＭＡＰ（１６２ｍｇ、１．３２ｍｍｏｌ）を加えた。４５分後、反応混合物を濃縮し、シリカゲルクロマトグラフィー（０−＞１５％ＥｔＯＡｃ／ヘキサン、線形勾配）で精製し、望ましい生成物が粘性の油として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝４９３。

Procedure To a solution of the amide from B1-5 (173 mg, 0.441 mmol) in 2.2 mL CH ₃ CN was added Boc ₂ O (289 mg, 1.32 mmol) and DMAP (162 mg, 1.32 mmol). After 45 minutes, the reaction mixture was concentrated and purified by silica gel chromatography (0-> 15% EtOAc / hexanes, linear gradient) to give the desired product as a viscous oil. LCMS [M + H] ⁺ = 493.

Procedure B1-7: tert-Butyl (3S) -5-methyl-3-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} -2-oxo-2,3,4,7-tetrahydro- 1H-azepine-1-carboxylate

手順Ｂ１−６からのジエン（１２２ｍｇ、０．２４８ｍｍｏｌ）を４ｍＬの脱気したＣＨ_２Ｃｌ_２に入れた溶液に、グラブス第二世代メタセシス触媒（１４．７ｍｇ、０．０１７ｍｍｏｌ）（「Ｈａｎｄｂｏｏｋ ｏｆ Ｍｅｔａｔｈｅｓｉｓ；Ｇｒｕｂｂｓ，Ｒ．Ｈ．，Ｅｄ．；Ｗｉｌｅｙ−ＶＣＨ：Ｗｅｉｎｈｅｉｍ，２００３」、「Ｄｉｅｄｒｉｃｈ，Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．２００６，６２，１７７７−１７８６」）を１ｍＬの脱気したＣＨ_２Ｃｌ_２に入れたものを加えた。反応混合物を４０℃まで２時間加熱した後、室温まで冷まし、シリカゲルクロマトグラフィー（０−＞２０％ＥｔＯＡｃ／ヘキサン、線形勾配）により直接精製し、望ましいラクタムＢ−７が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝４６５。

To a solution of the diene from Procedure B1-6 (122 mg, 0.248 mmol) in 4 mL of degassed CH ₂ Cl ₂ , Grubbs second generation metathesis catalyst (14.7 mg, 0.017 mmol) (“Handbook of Metathesis” ; Grubbs, R.H., Ed; Wiley -VCH:. Weinheim, 2003 "," Diedrich, Tetrahedron Lett.2006, 62, those placed 1777-1786 ") in _CH 2 Cl ₂ was degassed 1mL added. The reaction mixture was heated to 40 ° C. for 2 hours, then cooled to room temperature and purified directly by silica gel chromatography (0-> 20% EtOAc / hexane, linear gradient) to give the desired lactam B-7 as a white solid. . LCMS [M + H] ⁺ = 465.

Procedure B1-8: tert-butyl ((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} hex-2-en-1-yl) Carbamate

上記の手順Ｂ１−７からのラクタム（４９ｍｇ、０．１０５ｍｍｏｌ）を２．１ｍＬ ＥｔＯＨに入れた溶液に、ＮａＢＨ_４（１６ｍｇ、０．４２２ｍｍｏｌ）を一度に加えた。反応を室温で１６時間進行させた後、ＥｔＯＡｃで希釈した。有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（５−＞３０％ＥｔＯＡｃ／ヘキサン、線形勾配）により精製し、望ましい生成物が粘性の油として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝４６９。

To a solution of the lactam from Procedure B1-7 above (49 mg, 0.105 mmol) in 2.1 mL EtOH was added NaBH ₄ (16 mg, 0.422 mmol) in one portion. The reaction was allowed to proceed for 16 hours at room temperature and then diluted with EtOAc. The organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (5-> 30% EtOAc / hexanes, linear gradient) to give the desired product as a viscous oil. LCMS [M + H] ⁺ = 469.

Procedure B1-9: tert-butyl ((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} hexyl) carbamate

手順Ｂ１−８からの生成物（３５ｍｇ、０．０７５ｍｍｏｌ）を１．５ｍＬ ＥｔＯＨに入れた溶液に、２０％の炭素担持Ｐｄ（ＯＨ）_２（５．２ｍｇ、７．４７μｍｏｌ）を加えた。水素バルーンを取り付け、反応混合物を水素（３ｘ）に排除／開放した。３時間後、容器をアルゴン（３ｘ）で排除／再充填した後、セライトのパッドを通過させて濾過し、ＥｔＯＡｃで濯いだ。混合した濾液を濃縮して、望ましい４−メチルリジン誘導体が粘性の油として、また新たに生成された立体中心を持つメチルでジアステレオマーの１：１の混合物として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝４７１。

To a solution of the product from Procedure B1-8 (35 mg, 0.075 mmol) in 1.5 mL EtOH was added 20% Pd (OH) _{2 on} carbon (5.2 mg, 7.47 μmol). A hydrogen balloon was attached and the reaction mixture was purged / opened to hydrogen (3x). After 3 hours, the vessel was evacuated / refilled with argon (3x), then filtered through a pad of celite and rinsed with EtOAc. The combined filtrates were concentrated to give the desired 4-methyllysine derivative as a viscous oil and as a 1: 1 mixture of methyl and diastereomers with newly formed stereocenters. LCMS [M + H] ⁺ = 471.

Procedure B1-10: N-[(1S) -5-amino-1- (hydroxymethyl) -3-methylpentyl] -4-methyl-N- (3-methylbutyl) benzenesulfonamide

手順Ｂ１−９からの生成物（３０ｍｇ、０．０６４ｍｍｏｌ）を１．２ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、ジオキサンに入れた０．４ｍＬ ４Ｍ ＨＣｌを加えた。２時間後、反応混合物を濃縮させて、表題の化合物が白色の固体として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝３７１。

To a solution of the product from Procedure B1-9 (30 mg, 0.064 mmol) in 1.2 mL CH ₂ Cl ₂ was added 0.4 mL 4M HCl in dioxane. After 2 hours, the reaction mixture was concentrated to give the title compound as a white solid. LCMS [M + H] ⁺ = 371.

Procedure B1-11: tert-butyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-3-methyl-5- (3-methylbutyl) [(4-methylphenyl) Sulfonyl] amino} hexyl) amino] -2-oxoethyl} carbamate

手順Ｂ１−１０からのアミン（２９ｍｇ、０．０７１ｍｍｏｌ）およびＮ−Ｂｏｃ−（Ｓ）−ジフェニルアラニン（２９ｍｇ、０．０８６ｍｍｏｌ）を１．４ｍＬ ＤＭＦに入れた溶液に、トリエチルアミン（０．０４０ｍＬ、０．２８５ｍｍｏｌ）およびＢＯＰ試薬（４４．１ｍｇ、０．１００ｍｍｏｌ）を加えた。５０分後、反応混合物をＥｔＯＡｃで希釈し、有機物をＨ_２Ｏ、３Ｍ ＬｉＣｌ（３ｘ）およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（３０−＞７０％ＥｔＯＡｃ／ヘキサン、線形勾配）により精製し、望ましい付加物が粘性の油として得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６９４。

To a solution of amine from Procedure B1-10 (29 mg, 0.071 mmol) and N-Boc- (S) -diphenylalanine (29 mg, 0.086 mmol) in 1.4 mL DMF was added triethylamine (0.040 mL, 0 .285 mmol) and BOP reagent (44.1 mg, 0.100 mmol) were added. After 50 minutes, the reaction mixture was diluted with EtOAc and the organics were washed with H ₂ O, 3M LiCl (3 ×) and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (30-> 70% EtOAc / hexanes, linear gradient) to give the desired adduct as a viscous oil. LCMS [M + H] ⁺ = 694.

Procedure B1-12: (2S) -2-amino-N-((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) -sulfonyl] amino} hexyl) −3,3-Diphenylpropanamide To a solution of the product from Procedure B1-11 (34 mg, 0.049 mmol) in 0.7 mL CH ₂ Cl ₂ was added 0.6 mL 4M HCl in dioxane. After 1.5 hours at room temperature, the reaction mixture was concentrated to give the desired product as a white solid. The ¹ H NMR data in the table below is for a 1: 1 ratio of diastereomers from the synthesis of lysine derivatives used in the above procedure. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.17 (m, 4H), 7.72 (m, 2H), 7.52 to 7.43 (m, 4H), 7.26 to 7.21 ( m, 2H), 3.82 (m, 1H), 3.76 (d, J = 5.5 Hz, 1H), 3.61 (d, J = 5.7 Hz), 3.39 (m, 2H) 3.11 to 2.80 Hz (m, 4H), 2.38 (d, J = 8.5 Hz, 3H), 2.15 to 1.99 (m, 2H), 1.47 (m, 3H) , 0.85 (m, 6H), 0.70 (m, 2H), LCMS [M + H] ⁺ = 593.

Example B2
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-3-methyl-5-{(3-methyl-butyl) [(4-methylphenyl) sulfonyl] amino} Hexylamino] -2-oxoethyl} carbamate

実施例Ｂ１、手順１０からのアミン（２６ｍｇ、０．０４１ｍｍｏｌ）を０．８３ｍＬ ＣＨＣｌ_３に入れた溶液に、０．２１ｍＬの飽和したＮａＨＣＯ_３溶液を加えた。クロロギ酸メチル（０．００７ｍＬ、０．０８３ｍｍｏｌ）を加え、反応を室温で３時間進行させた。混合物をＣＨＣｌ_３およびブラインで希釈し、層を分離した。水相をＣＨＣｌ_３（３ｘ）で洗浄し、および混合した有機物をＮａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。ＨＰＬＣによるジアステレオマーの分離（Ｓｕｎｆｉｒｅカラム、１５ｍＬ／分）により、凍結乾燥後に、望ましい生成物が白色の固体として得られた。逆相での溶出が速いジアステレオマーについての特性データ。^１Ｈ ＮＭＲ（４００ＭＨｚ、ｄ_４−ＭｅＯＨ）δ７．７０（ｄ、Ｊ＝８．３Ｈｚ、２Ｈ）、７．３４から７．３１（ｍ、４Ｈ）、７．２２から７．１０（ｍ、８Ｈ）、４．８７（ｄ、Ｊ＝１０．３Ｈｚ、１Ｈ）、４．２６（ｄ、Ｊ＝１１．４Ｈｚ）、３．７３（ｍ、１Ｈ）、３．５０（ｓ、３Ｈ）、３．３６から３．２８（ｍ、２Ｈ）、３．１７から３．００（ｍ、４Ｈ）、２．８０（ｍ、２Ｈ）、１．４８（ｍ、２Ｈ）、１．３９から１．２９（ｍ、３Ｈ）、１．２１から１．１８（ｍ、２Ｈ）、１．００（ｍ、１Ｈ）、０．８７（ｄ、Ｊ＝６．１Ｈｚ、６Ｈ）、０．６５（ｄ、Ｊ＝５．６Ｈｚ、３Ｈ）。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６５２。逆相での溶出が遅いジアステレオマーについての特性データ。^１Ｈ ＮＭＲ（４００ＭＨｚ、ｄ_４−ＭｅＯＨ）δ７．７０（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、７．３０から７．１９（ｍ、１０Ｈ）、７．１６から７．１２（ｍ、２Ｈ）、４．８７（ｄ、Ｊ＝１０．１Ｈｚ、１Ｈ）、４．２８（ｄ、Ｊ＝１１．２Ｈｚ）、３．７２（ｍ、１Ｈ）、３．４８（ｓ、３Ｈ）、３．６３から３．５３（ｍ、２Ｈ）、３．１９から３．１０（ｍ、２Ｈ）、２．９４（ｍ、１Ｈ）、２．６４（ｍ、１Ｈ）、１．５３（ｍ、３Ｈ）、１．４３から１．３７（ｍ、２Ｈ）、１．１０（ｍ、３Ｈ）、０．８７（ｄ、Ｊ＝５．６Ｈｚ、６Ｈ）、０．６９（ｄ、Ｊ＝６．１Ｈｚ、３Ｈ）。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６５２。

To a solution of the amine from Example B1, Procedure 10 (26 mg, 0.041 mmol) in 0.83 mL CHCl ₃ was added 0.21 mL saturated NaHCO ₃ solution. Methyl chloroformate (0.007 mL, 0.083 mmol) was added and the reaction was allowed to proceed for 3 hours at room temperature. The mixture was diluted with CHCl ₃ and brine and the layers were separated. The aqueous phase was washed with CHCl ₃ (3 ×) and the combined organics were dried over Na ₂ SO ₄ , filtered and concentrated. Separation of diastereomers by HPLC (Sunfire column, 15 mL / min) gave the desired product as a white solid after lyophilization. Characteristic data for diastereomers that elute quickly in reverse phase. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.70 (d, J = 8.3 Hz, 2H), 7.34 to 7.31 (m, 4H), 7.22 to 7.10 (m, 8H) ), 4.87 (d, J = 10.3 Hz, 1H), 4.26 (d, J = 11.4 Hz), 3.73 (m, 1H), 3.50 (s, 3H), 3. 36 to 3.28 (m, 2H), 3.17 to 3.00 (m, 4H), 2.80 (m, 2H), 1.48 (m, 2H), 1.39 to 1.29 ( m, 3H), 1.21 to 1.18 (m, 2H), 1.00 (m, 1H), 0.87 (d, J = 6.1 Hz, 6H), 0.65 (d, J = 5.6Hz, 3H). LCMS [M + H] ⁺ = 652. Characteristic data for diastereomers with slow elution in reverse phase. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.70 (d, J = 8.0 Hz, 2H), 7.30 to 7.19 (m, 10H), 7.16 to 7.12 (m, 2H ), 4.87 (d, J = 10.1 Hz, 1H), 4.28 (d, J = 11.2 Hz), 3.72 (m, 1H), 3.48 (s, 3H), 3. 63 to 3.53 (m, 2H), 3.19 to 3.10 (m, 2H), 2.94 (m, 1H), 2.64 (m, 1H), 1.53 (m, 3H) 1.43 to 1.37 (m, 2H), 1.10 (m, 3H), 0.87 (d, J = 5.6 Hz, 6H), 0.69 (d, J = 6.1 Hz, 3H). LCMS [M + H] ⁺ = 652.

Example C1
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-2-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} hexylamino ] -2-oxoethyl} carbamate

手順Ｃ１−１：メチル（２Ｓ）−２−｛［（４−メチルフェニル）スルホニル］アミノ｝ペント−４−エン酸塩

Procedure C1-1: Methyl (2S) -2-{[(4-methylphenyl) sulfonyl] amino} pent-4-enoic acid salt

７．３５ｇ（４４．４ｍｍｏｌ）のアリルグリシンメチルエステル塩酸塩を４００ｍＬのＤＣＭに含む溶液に、１２．３ｍＬ（８９ｍｍｏｌ）のトリエチルアミンを加えた後、８．５ｇ（４４．４ｍｍｏｌ）のトシル塩化物を加え、結果として生じる混合物を室温で１６時間攪拌させた。溶液を、１ Ｎ ＨＣｌ（２×５０ｍＬ）、飽和ＮａＨＣＯ_３（２×５０ｍＬ）、水（５０ｍＬ）、およびブライン（５０ｍＬ）で洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝２８４．３。

To a solution of 7.35 g (44.4 mmol) of allylglycine methyl ester hydrochloride in 400 mL of DCM was added 12.3 mL (89 mmol) of triethylamine followed by 8.5 g (44.4 mmol) of tosyl chloride. In addition, the resulting mixture was allowed to stir at room temperature for 16 hours. The solution was washed with 1 N HCl (2 × 50 mL), saturated NaHCO ₃ (2 × 50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over MgSO ₄ , concentrated and separated by chromatography (0% to 100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 284.3.

Procedure C1-2: Methyl (2S) -2-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} pent-4-enoate

手順Ｃ１−１からのスルホンアミド（６．０ｇ、２１．２ｍｍｏｌ）を８５ｍＬのＤＣＭに溶解し、トリフェニルホスフィン（６．６６ｇ、２５．４ｍｍｏｌ）、イソアミルアルコール（２．８ｍＬ、２５．４ｍｍｏｌ）、およびＤＣＡＤ（９．３３ｇ、２５．４ｍｍｏｌ）で順に処理し、結果として生じる溶液を室温で７２時間攪拌させた。結果として生じる固体を濾過して捨て、ろ液を濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝３５４．５。

The sulfonamide from procedure C1-1 (6.0 g, 21.2 mmol) was dissolved in 85 mL DCM and triphenylphosphine (6.66 g, 25.4 mmol), isoamyl alcohol (2.8 mL, 25.4 mmol), And DCAD (9.33 g, 25.4 mmol) in turn and the resulting solution was allowed to stir at room temperature for 72 hours. The resulting solid was filtered off and the filtrate was concentrated and separated by chromatography (0% to 100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 354.5.

Procedure C1-3: (2S) -2-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} pent-4-enoic acid

手順Ｃ１−２からのエステル２．８９ｇ（８．１８ｍｍｏｌ）を含む溶液を１０ｍＬのＴＨＦに溶解したものと１０ｍＬの水を、８．１８ｍＬ（１６．３ｍｍｏｌ）の２Ｎ ＬｉＯＨで処理し、結果として生じる混合物を室温で１６時間攪拌した。混合物を３Ｎ ＨＣｌで酸性化し、エーテル（３×３ｍＬ）で洗浄した。混合した有機物をＭｇＳＯ_４上で乾燥させ、濃縮させて、望ましい酸が得られた。ＬＣＭＳ（Ｍ＋１）＝３４０．４。

Treatment of a solution containing 2.89 g (8.18 mmol) of ester from Procedure C1-2 in 10 mL of THF and 10 mL of water results in 8.18 mL (16.3 mmol) of 2N LiOH, resulting in The mixture was stirred at room temperature for 16 hours. The mixture was acidified with 3N HCl and washed with ether (3 × 3 mL). The combined organics were dried over MgSO ₄ and concentrated to give the desired acid. LCMS (M + 1) = 340.4.

Procedure C1-4: (2S) -N- (2,4-dimethoxybenzyl) -2-{(3-methylbutyl) [4-methylphenyl) sulfonyl] amino} -N- (2-methylprop-2-ene- 1-yl) pent-4-enamide

手順Ｃ１−３からのカルボン酸（１．５７ｇ（４．６２ｍｍｏｌ）を８０ｍＬのＤＣＭに入れた溶液に、０．９３ｇ（４．２ｍｍｏｌ）のＮ−（２，４−ジメトキシベンジル）−２−メチルプロパ−２−エン−１−アミン（中間体１）および０．８９ｇ（４．６２ｍｍｏｌ）のＥＤＣを加えた。結果として生じる混合物を室温で１６時間攪拌し、濃縮し、直接クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましいアミドが白色の固体として得られた。ＬＣＭＳ（Ｍ＋１）＝５４３．７。

To a solution of the carboxylic acid from Procedure C1-3 (1.57 g (4.62 mmol) in 80 mL DCM was added 0.93 g (4.2 mmol) N- (2,4-dimethoxybenzyl) -2-methylprop 2-ene-1-amine (Intermediate 1) and 0.89 g (4.62 mmol) of EDC were added and the resulting mixture was stirred at room temperature for 16 h, concentrated and directly chromatographed (from 0% (100% EtOAc / hexanes) to give the desired amide as a white solid, LCMS (M + 1) = 543.7.

Procedure C1-5: (3S) -1- (2,4-dimethoxybenzyl) -6-methyl-3-[(3-methylbutyl) (4-methylphenyl) sulfonyl) amino] -1,3,4,7 -Tetrahydro-2H-azepin-2-one

上記の手順Ｃ１−４から得られた０．９８８ｇ（１．８２ｍｍｏｌ）のジエンを含む溶液を２７０ｍＬのＤＣＭに溶解したものを、０．３８６ｇ（０．４５５ｍｍｏｌ）の第二世代グラブス触媒で処理した。反応混合物を４０℃で１６時間加熱してから冷まし、濃縮し、クロマトグラフィー（勾配：０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましいラクタムが得られた。ＬＣＭＳ（Ｍ＋１）＝５１５．７。

A solution containing 0.988 g (1.82 mmol) of the diene obtained from Procedure C1-4 above was dissolved in 270 mL of DCM and treated with 0.386 g (0.455 mmol) of the second generation Grubbs catalyst. . The reaction mixture was heated at 40 ° C. for 16 hours, then cooled, concentrated and separated by chromatography (gradient: 0% to 100% EtOAc / hexanes) to give the desired lactam. LCMS (M + 1) = 515.7.

Procedure C1-6: 4-Methyl-N- (3-methylbutyl) -N-[(3S) -6-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl] Benzenesulfonamide

０．７８ｇ（１．５１ｍｍｏｌ）のラクタムＣ１−５を含む溶液を９ｍＬのＤＣＭに溶解したものを、１３ｍＬのＴＦＡで処理し、１６時間攪拌した。結果的に生じる紫色の溶液を濃縮し、３０ｍＬのメタノールで処理してから濾過した。ろ液を濃縮し、２０ｍＬのＤＣＭで希釈し、水（ｘ２）、飽和重炭酸塩溶液（ｘ２）およびブラインで洗浄した。有機抽出物を乾燥させ、濃縮し、クロマトグラフィー（勾配：０％から１００％ＥｔＯＡｃ／ヘキサン）で分離して、望ましいラクタムが得られた。ＬＣＭＳ（Ｍ＋１）＝３６５．５。

A solution containing 0.78 g (1.51 mmol) of lactam C1-5 dissolved in 9 mL of DCM was treated with 13 mL of TFA and stirred for 16 hours. The resulting purple solution was concentrated, treated with 30 mL of methanol and then filtered. The filtrate was concentrated, diluted with 20 mL DCM and washed with water (x2), saturated bicarbonate solution (x2) and brine. The organic extract was dried, concentrated and separated by chromatography (gradient: 0% to 100% EtOAc / hexanes) to give the desired lactam. LCMS (M + l) = 365.5.

Procedure C1-7: 4-Methyl-N- (3-methylbutyl) -N-[(3S) -6-methyl-2-oxoazepan-3-yl] benzenesulfonamide

手順Ｃ１−６からの０．５１ｇ（１．４ｍｍｏｌ）のラクタムを含む脱気した溶液を１０ｍＬのＥｔＯＡｃに溶解したものを、１７ｍｇの１０％炭素担持Ｐｄで処理し、ＳＴＰで１６時間水素化した。反応混合物をセライトを通過させて濾過し、蒸発させて、望ましい化合物を残した。ＬＣＭＳ（Ｍ＋１）＝３６７．５。

A degassed solution containing 0.51 g (1.4 mmol) of lactam from Procedure C1-6 dissolved in 10 mL of EtOAc was treated with 17 mg of 10% Pd on carbon and hydrogenated with STP for 16 hours. . The reaction mixture was filtered through celite and evaporated to leave the desired compound. LCMS (M + 1) = 367.5.

Procedure C1-8: tert-Butyl (3S) -6-methyl-3-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} -2-oxoazepane-1-carboxylate

上記の手順Ｃ１−７から得られたラクタム（０．５１ｇ、１．４ｍｍｏｌ）を８ｍＬのＭｅＣＮに溶解し、０．９１１ｇ（４．１７ｍｍｏｌ）のＢｏｃ_２Ｏで処理した後、１７ｍｇ（０．１４ｍｍｏｌ）のＤＭＡＰで処理した。結果として生じる混合物を１６時間攪拌した後、濃縮させた。カラムクロマトグラフィー（勾配：０％から１００％ＥｔＯＡｃ／ヘキサン）により、望ましいラクタムが得られた。
ＬＣＭＳ（Ｍ＋１）＝４６７．７。

The lactam obtained from procedure C1-7 above (0.51 g, 1.4 mmol) was dissolved in 8 mL of MeCN and treated with 0.911 g (4.17 mmol) of Boc ₂ O, followed by 17 mg (0.14 mmol). ) DMAP. The resulting mixture was stirred for 16 hours and then concentrated. Column chromatography (gradient: 0% to 100% EtOAc / hexanes) gave the desired lactam.
LCMS (M + 1) = 467.7.

Procedure C1-9: tert-butyl ((5S) -6-hydroxy-2-methyl-5-{(3-methylbutyl) [4-methylphenyl) sulfonyl] amino} hexyl) carbamate

手順Ｃ１−８からのラクタム（０．３４５ｇ、０．７３９）を４ｍＬのＥｔＯＨに入れた溶液に、０．０７８ｇ（２．０７ｍｍｏｌ）のＮａＢＨ_４を加えた。結果として生じる混合物を５時間攪拌し、濃縮させた。残留物を２ｍＬの１Ｎ ＮａＯＨで処理し、ＥｔＯＡｃ×３で抽出し、乾燥させ、濃縮させ、クロマトグラフィー（勾配：０％から１００％ＥｔＯＡｃ／ヘキサン）で分離して、望ましいアルコールが得られた。ＬＣＭＳ（Ｍ＋１）＝４７１．７。

To a solution of lactam from Procedure C1-8 (0.345 g, 0.739) in 4 mL EtOH was added 0.078 g (2.07 mmol) NaBH ₄ . The resulting mixture was stirred for 5 hours and concentrated. The residue was treated with 2 mL of 1N NaOH, extracted with EtOAc × 3, dried, concentrated and separated by chromatography (gradient: 0% to 100% EtOAc / hexanes) to give the desired alcohol. LCMS (M + 1) = 471.7.

Procedure C1-10: N-[(1S) -5-amino-1- (hydroxymethyl) -4-methylpentyl] -4-methyl-N- (3-methylbutyl) benzenesulfonamide

手順Ｃ１−９からの０．２３ｇ（０．４９ｍｍｏｌ）の保護アミンを含む溶液を４ｍＬのＤＣＭに溶かした溶液に、２ｍＬのＴＦＡを加えた。反応混合物を３０分間攪拌した後、固体 Ｋ_２ＣＯ_３を加えて塩基性にした。ＤＣＭ（３×５ｍＬ）での抽出により、望ましいアミノアルコールが油として得られた。ＬＣＭＳ（Ｍ＋１）＝３７１．５。

To a solution of 0.23 g (0.49 mmol) of the protected amine from Procedure C1-9 in 4 mL DCM was added 2 mL TFA. The reaction mixture was stirred for 30 minutes and then made basic by the addition of solid K ₂ CO ₃ . Extraction with DCM (3 × 5 mL) gave the desired amino alcohol as an oil. LCMS (M + 1) = 371.5.

Procedure C1-11: methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-2-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] ] Amino} hexylamino] -2-oxoethyl} carbamate Amine from procedure C1-10 (181 mg, 0.488 mmol) and N-Moc- (S) -diphenylalanine (146 mg, 0.488 mmol) in 3 mL DMF. To the charged solution was added diisopropylethylamine (164 mg, 1.27 mmol) and BOP reagent (281 mg, 0.635 mmol) After 60 minutes, the reaction mixture was filtered and the residue was purified by reverse phase chromatography. a portion was diluted with EtOAc, and the addition of saturated NaHCO _3, and _basic. the organic phase ^. Apart, dried, evaporated, the desired adduct as a white solid _{1 H NMR (CDCl 3):} δ7.73 from 7.71 (d, J = 7Hz, 2H), 7.50 To 7.05 (m, 12 H), 5.71 (br s, 1 H), 5.11 to 5.10 (m, 1 H), 4.82 to 4.76 (m, 1 H), 4. 49 to 4.47 (d, J = 10 Hz, 1H), 3.61 to 3.59 (m, 4H), 3.53 to 3.29 (m, 2H), 3.22 to 3.20 (m) 1H), 3.08 to 3.05 (m, 1H), 2.93 to 2.82 (m, 1H), 2.76 to 2.66 (m, 1H), 2.42 (s, 3H ), 2.34 to 2.24 (m, 1H), 1.56 to 1.21 (m, 6H), 0.91 to 0.90 (m, 6H), 0.77 Et 0.65 (m, 2H), 0.53 from ^{0.48 (m, 3H) .LCMS [} M + H] + = 652.9.

Example D1
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-methylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (Diphenylmethyl) -2-oxoethyl] carbamate and methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3R) -3-methylbutyl) Amino] -6-hydroxy-1-methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate

手順Ｄ１−１：１−ベンジル５−メチル（２Ｓ）−２−［ビス（ｔｅｒｔ−ブトキシカルボニル）アミノ］ペンタン二酸塩

Procedure D1-1: 1-Benzyl 5-methyl (2S) -2- [bis (tert-butoxycarbonyl) amino] pentanedioic acid salt

１０．０ｇ（２８．５ｍｍｏｌ）のベンジル５−メチル（２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ペンタン二酸塩（Ｓｃｈｏｅｎｆｅｌｄｅｒ ｅｔ ａｌ．，Ｓｙｎ Ｃｏｍｍ．１９９０，２０（１７），２５８５）を含む溶液を１００ｍＬのアセトニトリルに入れたものに、９．３ｇ（４２．７ｍｍｏｌ）のＢｏｃ_２Ｏを、次に１．７３ｇ（１４．２ｍｍｏｌ）のＤＭＡＰを加えた。結果として生じる混合物を１６時間攪拌し、濃縮させた。カラムクロマトグラフィー（３０％ＥｔＯＡｃ／ヘキサン）により、ビスＢｏｃアミンが得られた。ＬＣＭＳ（Ｍ＋Ｎａ）＝４７４．０。

10.0 g (28.5 mmol) of benzyl 5-methyl (2S) -2-[(tert-butoxycarbonyl) amino] pentanedioic acid salt (Schoenfelder et al., Syn Comm. 1990, 20 (17), 2585) 9.3 g (42.7 mmol) of Boc ₂ O and then 1.73 g (14.2 mmol) of DMAP were added to a solution of the solution in 100 mL of acetonitrile. The resulting mixture was stirred for 16 hours and concentrated. Column chromatography (30% EtOAc / hexane) gave bis Boc amine. LCMS (M + Na) = 474.0.

Procedure D1-2: (2S) -2- [Bis (tert-butoxycarbonyl) amino] -5-oxopentanoic acid benzyl

手順Ｄ１−１からの１１．０ｇ（２４．４ｍｍｏｌ）のジエステルを含む−７０℃の溶液を２５０ｍＬのエーテルに入れたものに、３１．７ｍＬのＤＩＢＡＬ−Ｈ（トルエン中１Ｍ）を加えた。反応混合物を５分間攪拌し、１０ｍＬの水で処理し、室温まで温めた。反応混合物をセライトを通過させて濾過し、蒸発させた。カラムクロマトグラフィー（３０％ＥｔＯＡｃ／ヘキサン）により、望ましいアルデヒドが得られた。ＬＣＭＳ（Ｍ＋Ｎａ）＝４４４．０。

To a solution of −70 ° C. containing 11.0 g (24.4 mmol) of diester from Procedure D1-1 in 250 mL of ether was added 31.7 mL of DIBAL-H (1M in toluene). The reaction mixture was stirred for 5 minutes, treated with 10 mL water and allowed to warm to room temperature. The reaction mixture was filtered through celite and evaporated. Column chromatography (30% EtOAc / hexane) provided the desired aldehyde. LCMS (M + Na) = 444.0.

Procedure D1-3: 2S) -2- [Bis (tert-butoxycarbonyl) amino] -6-nitrohepta-5-enoic acid benzyl

手順Ｄ１−２からのアルデヒド（８．３ｇ、１９．７ｍｍｏｌ）を５０ｍＬのトルエンに入れた溶液に、０℃で、１４．８ｇ（１９７ｍｍｏｌ）のニトロエタンを加えた後、０．４２ｍＬ（３．３５ｍｍｏｌ）のテトラメチルグアニジンを加えた。反応混合物を３０分間攪拌した後、４．１ｍＬ（２９．５ｍｍｏｌ）のＴＥＡおよび２．３ｍＬ（２９．５ｍｍｏｌ）の塩化メタンスルホニルで処理した。さらに２時間攪拌した後、１２２ｍｇ（１．００ｍｍｏｌ）のＤＭＡＰを加え、反応混合物を６０℃まで１６時間加熱した。反応混合物を冷まし、１００ｍＬのエーテルで希釈した。溶液を水（２×２５ｍＬ）、飽和ＮａＨＣＯ_３（２×２５ｍＬ）およびブラインで洗浄した。カラムクロマトグラフィー（３０％ＥｔＯＡｃ／ヘキサン）により、望ましいニトロオレフィンが得られた。
ＬＣＭＳ（Ｍ＋Ｎａ）＝５００．９。

To a solution of the aldehyde from Procedure D1-2 (8.3 g, 19.7 mmol) in 50 mL of toluene at 0 ° C. was added 14.8 g (197 mmol) of nitroethane, followed by 0.42 mL (3.35 mmol). ) Tetramethylguanidine. The reaction mixture was stirred for 30 minutes before being treated with 4.1 mL (29.5 mmol) TEA and 2.3 mL (29.5 mmol) methanesulfonyl chloride. After stirring for an additional 2 hours, 122 mg (1.00 mmol) of DMAP was added and the reaction mixture was heated to 60 ° C. for 16 hours. The reaction mixture was cooled and diluted with 100 mL of ether. The solution was washed with water (2 × 25 mL), saturated NaHCO ₃ (2 × 25 mL) and brine. Column chromatography (30% EtOAc / hexanes) gave the desired nitroolefin.
LCMS (M + Na) = 500.9.

Procedure D1-4: (2S) -6-amino-2- [bis (tert-butoxycarbonyl) amino] heptanoic acid

上記の手順３からのニトロオレフィン（９．０ｇ、１８．８ｍｍｏｌ）を２２５ｍＬのＭｅＯＨに溶解し、３ｇの１０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物をＳＴＰで７２時間水素化し、セライトのパッドを通過させて濾過し、蒸発させ、望ましいアミノ酸が白色の発泡剤として得られた。ＬＣＭＳ（Ｍ＋１）＝３６１．１。

The nitroolefin from Step 3 above (9.0 g, 18.8 mmol) was dissolved in 225 mL MeOH and treated with 3 g 10% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 72 hours, filtered through a pad of celite and evaporated to give the desired amino acid as a white blowing agent. LCMS (M + 1) = 361.1.

Procedure D1-5: (2S) -6-{[(Benzyloxy) carbonyl] amino} -2- [bis (tert-butoxycarbonyl) amino] heptanoic acid

Ｃｂｚ塩化物（１．２８ｍＬ、９．０ｍｍｏｌ）を７ｍＬのジオキサンに溶解し、手順Ｄ１−４からの２．７ｇ（７．４９ｍｍｏｌ）のアミンを１７１ｍＬの水／ジオキサン／アセトニトリル（７２／５４／４５）および７９４ｍｇ（７．４９ｍｍｏｌ）の炭酸ナトリウムに溶かしたものに加えた。反応混合物を１６時間攪拌し、濃縮させた。残留物を５０ｍＬのＤＣＭに再び溶解し、１％クエン酸溶液、ブラインの順に洗浄した。有機抽出物を乾燥させ、濃縮させて、望ましいＮ−Ｃｂｚ保護アミンＤ１−５を残した。ＬＣＭＳ（Ｍ＋１）＝４９５．６

Cbz chloride (1.28 mL, 9.0 mmol) was dissolved in 7 mL dioxane and 2.7 g (7.49 mmol) of amine from Procedure D1-4 was dissolved in 171 mL water / dioxane / acetonitrile (72/54/45). ) And 794 mg (7.49 mmol) of sodium carbonate. The reaction mixture was stirred for 16 hours and concentrated. The residue was redissolved in 50 mL DCM and washed sequentially with 1% citric acid solution and brine. The organic extract was dried and concentrated to leave the desired N-Cbz protected amine D1-5. LCMS (M + 1) = 495.6

Procedure D1-6: Methyl (2S) -2-amino-6-{[(benzyloxy) carbonyl] amino} heptanoate

化合物Ｄ１−５（２．８ｇ、５．６６ｍｍｏｌ）を５０ｍＬのＭｅＯＨに０℃で溶かし、溶液にＨＣｌガス流を２分間通過させた。反応混合物をさらに３０分間攪拌した後、溶剤を除去し、望ましいアミノエステル塩酸（ＨＣｌ）塩が得られたが、これをさらに精製することなく次の反応に使用した。ＬＣＭＳ（Ｍ＋１）＝３１０．４

Compound D1-5 (2.8 g, 5.66 mmol) was dissolved in 50 mL of MeOH at 0 ° C. and a stream of HCl gas was passed through the solution for 2 minutes. After stirring the reaction mixture for an additional 30 minutes, the solvent was removed to give the desired aminoester hydrochloride (HCl) salt, which was used in the next reaction without further purification. LCMS (M + 1) = 310.4

Procedure D1-7: Methyl (2S) -6-{[(benzyloxy) carbonyl] amino} -2-{[(4-nitrophenyl) sulfonyl] amino} heptanoate

２．４３ｇ（７．０５ｍｍｏｌ）のエステルＤ１−６を含む溶液を３５ｍＬのＤＣＭに入れたものに、２ｍＬ（１４ｍｍｏｌ）のトリエチルアミンを加えた後、１．５ｇ（７．０５ｍｍｏｌ）のｐ−塩化ニトロベンゼンスルホニルを加え、結果として生じる混合物を室温で１６時間攪拌させた。溶液を１ Ｎ ＨＣｌ（２×１０ｍＬ）、飽和ＮａＨＣＯ_３（２×１０ｍＬ）、水（１０ｍＬ）、およびブライン（１０ｍＬ）で洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物Ｄ１−７が得られた。ＬＣＭＳ（Ｍ＋１）＝４９４．５。

To a solution of 2.43 g (7.05 mmol) of ester D1-6 in 35 mL DCM was added 2 mL (14 mmol) triethylamine followed by 1.5 g (7.05 mmol) p-nitrochloride chloride. The sulfonyl was added and the resulting mixture was allowed to stir at room temperature for 16 hours. The solution was washed with 1 N HCl (2 × 10 mL), saturated NaHCO ₃ (2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over MgSO ₄ , concentrated, and chromatographed (0% to 100% EtOAc / hexanes) to give the desired product D1-7. LCMS (M + 1) = 494.5.

Procedure D1-8: Methyl (2S) -6-{[(benzyloxy) carbonyl] amino} -2-{(3-methylbutyl) [(4-nitrophenyl) sulfonyl] amino} heptanoate

スルホンアミドＤ１−７（０．８８ｇ、１．７８ｍｍｏｌ）を７ｍＬのＤＣＭに溶かし、トリフェニルホスフィン（５６１ｍｇ、２．１ｍｍｏｌ）、イソアミルアルコール（０．２３３ｍＬ、２．１４ｍｍｏｌ）、およびＤＣＡＤ（０．７８６ｇ、２．１４ｍｍｏｌ）で順に処理し、結果として生じる溶液を室温で７２時間攪拌させた。結果として生じる固体を濾過して捨て、ろ液を濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝５６４．６

Sulfonamide D1-7 (0.88 g, 1.78 mmol) was dissolved in 7 mL DCM, triphenylphosphine (561 mg, 2.1 mmol), isoamyl alcohol (0.233 mL, 2.14 mmol), and DCAD (0.786 g). , 2.14 mmol) and the resulting solution was allowed to stir at room temperature for 72 hours. The resulting solid was filtered off and the filtrate was concentrated and separated by chromatography (0% to 100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 564.6

Procedure D1-9: Methyl (2S) -6-amino} -2-[[(4-aminophenyl) sulfonyl] 3-methylbutyl) amino} heptanoate

０．７４８ｇ（１．３６ｍｍｏｌ）の化合物Ｄ１−８を含む脱気した溶液を２０ｍＬのＭｅＯＨに溶かしたものを、９５６ｍｇの１０％Ｐｄ（ＯＨ）_２で処理し、ＳＴＰで２時間水素化した。反応混合物をセライトを通過させて濾過し、蒸発させて、望ましい化合物Ｄ１−９を残した。ＬＣＭＳ（Ｍ＋１）＝４００．５。

A degassed solution containing 0.748 g (1.36 mmol) of compound D1-8 in 20 mL of MeOH was treated with 956 mg of 10% Pd (OH) ₂ and hydrogenated with STP for 2 hours. The reaction mixture was filtered through celite and evaporated to leave the desired compound D1-9. LCMS (M + 1) = 400.5.

Procedure D1-10: Methyl (2S) -2-[[(4-aminophenyl) sulfonyl] 3-methylbutyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3 -Diphenylpropanoyl} aminoheptanoate

手順Ｄ１−９からのアミン（３００ｍｇ、０．７５１ｍｍｏｌ）およびＮ−Ｍｏｃ−（Ｓ）−ジフェニルアラニン（２２５ｍｇ、０．７５１ｍｍｏｌ）を３ｍＬ ＤＣＭに入れた溶液に、ジイソプロピルエチルアミン（２５２ｍｇ、１．２９５ｍｍｏｌ）およびＢＯＰ試薬（４３２ｍｇ、０．９７６ｍｍｏｌ）を加えた。６０分後、反応混合物をＤＣＭで希釈し、飽和ＮａＨＣＯ_３で洗浄した。有機相を分離し、乾燥させ、蒸発させた。カラムクロマトグラフィー（勾配：０％から１００％ＥｔＯＡｃ／ヘキサン）望ましい付加物が白色の固体として得られた。ＬＣＭＳ（Ｍ＋１）＝６８１．８。

To a solution of the amine from Procedure D1-9 (300 mg, 0.751 mmol) and N-Moc- (S) -diphenylalanine (225 mg, 0.751 mmol) in 3 mL DCM was added diisopropylethylamine (252 mg, 1.295 mmol). And BOP reagent (432 mg, 0.976 mmol) were added. After 60 minutes, the reaction mixture was diluted with DCM and washed with saturated NaHCO ₃ . The organic phase was separated, dried and evaporated. Column chromatography (gradient: 0% to 100% EtOAc / hexanes) The desired adduct was obtained as a white solid. LCMS (M + 1) = 681.8.

Procedure D1-11: Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-methylbutyl) amino] -6-hydroxy-1-methyl (Hexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamic acid, and methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3R) -3-methylbutyl) amino] -6-hydroxy-1-methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate 485 mg (0.712 mmol) of ester obtained from procedure D1-10 0.71 mL of 2M LiBH ₄ was added to a solution of the solution in 5 mL of THF. The reaction mixture was allowed to stir for 5 minutes before 0.5 mL of MeOH was added. After stirring for an additional hour, 2 mL of NaHCO ₃ was added and the reaction mixture was diluted with EtOAc. The organic phase was separated, dried and then subjected to reverse phase chromatography. The pure portion was diluted with EtOAc and made basic by addition of saturated NaHCO _{3 .} The organic phase was separated, dried and evaporated to give 313 mg (67%) of the desired adduct as a white solid.
¹ H NMR (CDCl ₃ ): δ 7.61 to 7.59 (m, 2H), 7.33 to 7.17 (m, 10H), 6.72 to 6.66 (m, 2H), 5.33 To 5.15 (m, 1H), 4.78 to 4.74 (m, 1H), 4.47 to 4.40 (m, 2H), 4.22 (s, 1H), 3.70 to 3 .50 (m, 8H), 3.21 to 3.16 (m, 1H), 3.02 to 3.00 (m, 1H), 2.50 to 2.42 (m, 1H), 1.57 To 1.50 (m, 4H), 1.30 to 0.82 (m, 12H), 0.56 to 0.55 (m, 2H). LCMS [M + H] ⁺ = 653.8.

  The diastereomeric mixture was separated by chiral chromatography (Kromasil Chiral TBB, 25% IPA in CO2, first eluting compound collection time: 21.0 to 24.30 min, second eluting compound collection time: 25.0 To 28.0 minutes).

N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide (first eluting compound, D1- (S)). ¹ H NMR (CDCl ₃ ): δ 7.61 to 7.59 (m, 2H), 7.31 to 7.17 (m, 10H), 6.68 to 6.66 (m, 2H), 5.33 To 5.27 (m, 2H), 4.78 to 4.74 (t, J = 10 Hz, 1H), 4.40 to 4.38 (d, J = 10 Hz, 2H), 3.61 to 3. 50 (m, 8H), 3.20 to 3.15 (m, 1H), 3.04 to 2.77 (m, 3H), 1.55 to 1.49 (m, 3H), 1.32 0.86 (m, 12H), 0.56 to 0.55 (d, J = 6 Hz, 2H). LCMS [M + H] ⁺ = 653.1.

N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide (second eluting compound, D1- (R)). ¹ H NMR (CDCl ₃ ): δ 7.61 to 7.58 (m, 2H), 7.34 to 7.20 (m, 10H), 6.72 to 6.66 (m, 2H), 5.28 To 5.26 (d, J = 8 Hz, 1H), 5.16 to 5.15 (d, J = 8 Hz, 1H), 4.78 to 4.74 (t, J = 10 Hz, 1H), 4. 47 to 4.45 (d, J = 10 Hz, 1H), 3.72 to 3.49 (m, 8H), 3.24 to 3.18 (m, 1H), 3.02 to 2.60 (m) 3H), 1.56 to 1.50 (m, 3H), 1.26 to 0.83 (m, 13H), 0.55 to 0.51 (m, 2H). LCMS [M + H] ⁺ = 653.0.

Example D2
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-ethylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (Diphenylmethyl) -2-oxoethyl] carbamate

手順Ｄ２−１：メチル（２Ｓ）−２−［ビス（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−ニトロオクタン−５−エン酸塩

Procedure D2-1: Methyl (2S) -2- [bis (tert-butoxycarbonyl) amino] -6-nitrooctane-5-enoate

３．４ｇ（９．８ｍｍｏｌ）の（２Ｓ）−２−（ビス（ｔｅｒｔ−ブトキシカルボニル）アミノ）−５−オキソペンタン酸塩（Ｔｅｔｒａｈｅｄｒｏｎ：Ａｓｙｍｍｅｔｒｙ １９９８，９（１９），３３８１−３３９４）を含む溶液を０℃で３５ｍＬのトルエンに入れたものに、８．８ｇ（９７ｍｍｏｌ）のニトロプロパンを加えた後、０．１１３ｇ（０．９８４ｍｍｏｌ）のテトラメチルグアニジンを加えた。反応混合物を３０分間攪拌した後、１．５ｇ（１４．８ｍｍｏｌ）のＴＥＡおよび１．７ｍＬ（１４．８ｍｍｏｌ）の塩化メタンスルホニルで処理した。さらに２時間攪拌した後、１２２ｍｇ（１．００ｍｍｏｌ）のＤＭＡＰを加え、反応混合物を６０℃まで１６時間加熱した。次に、反応混合物を室温まで冷まし、１００ｍＬのＥｔ_２Ｏで希釈した。溶液を水（２×２５ｍＬ）、飽和ＮａＨＣＯ_３（２×２５ｍＬ）およびブラインで洗浄した。洗浄した溶液のカラムクロマトグラフィー（２０％ＥｔＯＡｃ／ヘキサン）により、望ましいニトロオレフィンが得られた。ＬＣＭＳ（Ｍ＋Ｎａ）＝４４０。

A solution containing 3.4 g (9.8 mmol) of (2S) -2- (bis (tert-butoxycarbonyl) amino) -5-oxopentanoate (Tetrahedron: Asymmetry 1998, 9 (19), 3381-3394) Was added to 35 mL of toluene at 0 ° C., followed by the addition of 8.8 g (97 mmol) of nitropropane followed by 0.113 g (0.984 mmol) of tetramethylguanidine. The reaction mixture was stirred for 30 minutes before being treated with 1.5 g (14.8 mmol) TEA and 1.7 mL (14.8 mmol) methanesulfonyl chloride. After stirring for an additional 2 hours, 122 mg (1.00 mmol) of DMAP was added and the reaction mixture was heated to 60 ° C. for 16 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL Et ₂ O. The solution was washed with water (2 × 25 mL), saturated NaHCO ₃ (2 × 25 mL) and brine. Column chromatography (20% EtOAc / hexanes) of the washed solution gave the desired nitroolefin. LCMS (M + Na) = 440.

Procedure D2-2: Methyl (2S) -7-amino-2- [bis (tert-butoxycarbonyl) amino] octanoate

Ｄ１−１からのニトロオレフィン（１．８ｇ、４．３２ｍｍｏｌ）を３５ｍＬのＭｅＯＨに溶解し、１．５ｇの１０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物を、ＳＴＰで７２時間水素化し、セライトのパッドを通過させて濾過し、蒸発させて、望ましいアミノエステルが白色の発泡剤として得られた。ＬＣＭＳ（Ｍ＋１）＝３８９．０。

The nitroolefin from D1-1 (1.8 g, 4.32 mmol) was dissolved in 35 mL MeOH and treated with 1.5 g 10% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 72 hours, filtered through a pad of celite and evaporated to give the desired amino ester as a white blowing agent. LCMS (M + 1) = 389.0.

Procedure D2-3: Methyl (2S) -2- [bis (tert-butoxycarbonyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino ) Octanoate

２．２ｇ（５．６６ｍｍｏｌ）の上記アミンを含む溶液を、飽和ＮａＨＣＯ_３、アセトン、およびＴＨＦ（２４ｍＬ）１／１／１混合物に入れたものに、Ｍｏｃ−ジ−Ｐｈｅ−ＨＳＵエステル（２．２ｇ、５．６６ｍｍｏｌ）を加え、混合物を５時間撹拌した。生成物をＥｔＯＡｃに抽出し、有機相を乾燥させ、濃縮させて、さらに精製することなくそのまま使用した。ＬＣＭＳ（Ｍ＋Ｎａ）＝６９２

A solution containing 2.2 g (5.66 mmol) of the above amine in a mixture of saturated NaHCO ₃ , acetone, and THF (24 mL) 1/1/1 was added to the Moc-di-Phe-HSU ester (2. 2 g, 5.66 mmol) was added and the mixture was stirred for 5 hours. The product was extracted into EtOAc and the organic phase was dried, concentrated and used as is without further purification. LCMS (M + Na) = 692

Procedure D2-4: Methyl (2S) -2-amino-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino) octanoate

化合物Ｄ２−３（３．７ｇ、５．５２ｍｍｏｌ）を１０ｍＬのエーテルに２４℃で溶かし、ジオキサンに入れた１３．８ｍＬ（５５．２ｍｍｏｌ）の４Ｎ ＨＣｌで処理した。溶解が完了した後、反応混合物を３０分間［原文ママ］、溶剤を除去し、望ましいアミノエステル塩酸（ＨＣｌ）塩が得られたが、これをさらに精製することなく次の反応に使用した。ＬＣＭＳ（Ｍ＋１）＝４７０．０

Compound D2-3 (3.7 g, 5.52 mmol) was dissolved in 10 mL of ether at 24 ° C. and treated with 13.8 mL (55.2 mmol) of 4N HCl in dioxane. After dissolution was complete, the reaction mixture was removed for 30 min [original text] and the solvent was removed to give the desired aminoester hydrochloride (HCl) salt, which was used in the next reaction without further purification. LCMS (M + 1) = 470.0

Procedure D2-5: Methyl (2S, 6S) -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino) -2-{[(4-nitrophenyl ) Sulfonyl] amino} octanoate

２．８ｇ（５．５３ｍｍｏｌ）のエステルＤ２−４を含む溶液を５０ｍＬのクロロホルムに入れたものに、２ｍＬ（１４ｍｍｏｌ）のトリエチルアミンを加えた後、１．５４ｇ（６．１ｍｍｏｌ）のｐ−塩化ニトロベンゼンスルホニルを加え、結果として生じる混合物を室温で１６時間攪拌させた。次に、溶液を１ Ｎ ＨＣｌ（２×１０ｍＬ）、飽和ＮａＨＣＯ_３（２×１０ｍＬ）、水（１０ｍＬ）、およびブライン（１０ｍＬ）で洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、それぞれのジアステレオ異性生成物が白色の発泡剤として得られた。極性の低い生成物（８０％ＥｔＯＡｃ／ヘキサン）はＳ，Ｒ−異性体で、極性の高い生成物（８０％ＥｔＯＡｃ／ヘキサン）はＳ，Ｓ−異性体である。ＬＣＭＳ（Ｍ＋１）＝６５５。

To a solution of 2.8 g (5.53 mmol) of ester D2-4 in 50 mL of chloroform was added 2 mL (14 mmol) of triethylamine, followed by 1.54 g (6.1 mmol) of p-nitrochloride chloride. The sulfonyl was added and the resulting mixture was allowed to stir at room temperature for 16 hours. The solution was then washed with 1 N HCl (2 × 10 mL), saturated NaHCO ₃ (2 × 10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over MgSO ₄ , concentrated and separated by chromatography (0-100% EtOAc / hexanes) to give the respective diastereoisomeric product as a white blowing agent. The less polar product (80% EtOAc / hexane) is the S, R-isomer and the more polar product (80% EtOAc / hexane) is the S, S-isomer. LCMS (M + 1) = 655.

Procedure D2-6: Methyl (2S, 6S) -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenyl-propanoyl} amino) -2-{(3-methylbutyl) [ (4-Nitrophenyl) sulfonyl] amino} octanoate

極性の高いジアステレオ異性スルホンアミドＤ２−５（１．２ｇ、１．８ｍｍｏｌ）を１０ｍＬのＴＨＦに溶かし、トリフェニルホスフィン（５７７ｍｇ、２．２ｍｍｏｌ）、イソアミルアルコール（０．２３３ｍＬ、２．１４ｍｍｏｌ）、およびＤＩＡＤ（０．４４５ｇ、２．２ｍｍｏｌ）で順に処理し、結果として生じる溶液を室温で７２時間攪拌させた。混合物を濃縮し、クロマトグラフィー（０％から１００％ＥｔＯＡｃ／ヘキサン）で分離し、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝７２５．０

Highly polar diastereoisomeric sulfonamide D2-5 (1.2 g, 1.8 mmol) is dissolved in 10 mL of THF, triphenylphosphine (577 mg, 2.2 mmol), isoamyl alcohol (0.233 mL, 2.14 mmol), And DIAD (0.445 g, 2.2 mmol) in turn and the resulting solution was allowed to stir at room temperature for 72 hours. The mixture was concentrated and separated by chromatography (0-100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 725.0

Procedure D2-7: Methyl (2S, 6S) -2-[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino-6-({(2S) -2-[(methoxycarbonyl) amino] -3, 3-diphenylpropanoyl} amino) octanoate

１．０ｇ（１．３８ｍｍｏｌ）の化合物Ｄ２−６を含む脱気した溶液を、３０ｍＬのＭｅＯＨに溶かしたものを、９５６ｍｇの１０％Ｐｄ（ＯＨ）_２で処理し、ＳＴＰで室温で１時間水素化した。反応混合物をセライトを通過させて濾過し、蒸発させて、望ましい化合物を残した。ＬＣＭＳ（Ｍ＋１）＝６９５．０

A degassed solution containing 1.0 g (1.38 mmol) of compound D2-6 in 30 mL of MeOH was treated with 956 mg of 10% Pd (OH) ₂ and hydrogenated with STP at room temperature for 1 hour. Turned into. The reaction mixture was filtered through celite and evaporated to leave the desired compound. LCMS (M + 1) = 695.0

Procedure D2-8: Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-ethylbutyl) amino] -6-hydroxy-1-methyl (Hexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate salt 700 mg (1.0 mmol) of the ester from Procedure D2-7 in 10 mL of THF was added 1.2 mL of 2M. LiBH ₄ was added. The reaction mixture was allowed to stir for 5 minutes before 0.5 mL of MeOH was added. After stirring for an additional hour, 2 mL of NaHCO ₃ was added and the reaction mixture was diluted with EtOAc. The organic phase was separated, dried and then subjected to reverse phase chromatography. The pure portion was diluted with EtOAc and made basic by addition of saturated NaHCO _{3 .} The organic phase was separated, dried and evaporated to give the desired adduct as a white solid.
¹ H NMR (CDCl ₃ ): δ 7.61 (d, J = 7.8 Hz, 2H), 7.4 to 7.1 (m, 10H), 6.72 (d, J = 7.8 Hz, 2H) 5.25 (bt, 1H), 4.78 (t, 1H), 4.40 (d, J = 8 Hz, 2H), 4.21 (bs, 2H), 3.70 to 3.50 (m) 8H), 3.21 to 3.16 (m, 1H), 3.02 to 3.00 (m, 1H), 1.60 to 1.48 (m, 4H), 1.40 to 0.82 (M, 4H), 0, 75 (d, 6H), 0.56 to 0.55 (t, 3H). LCMS [M + H] ^< +> = 667.8.

Example D3
N-{(1S, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -Na- (methoxycarbonyl)- b-Phenyl-L-phenylalaninamide

メチル［（１Ｓ）−２−（｛（５Ｓ）−５−［［４−アミノフェニル）スルホニル］−（（３Ｓ）−３−エチルブチル）アミノ］−６−ヒドロキシ−１−メチルヘキシル）アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩（２２０ｍｇ、０．３３ｍｍｏｌ、実施例Ｄ２）を８ｍＬのＭｅＣＮに入れた溶液に、１１７ｍｇ（０．３３０ｍｍｏｌ）のＳｅｌｅｃｔｆｌｕｏｒ（登録商標）（すなわち、１−クロロメチル−４−フルオロ−１，４−ジアゾニアビシクロ［２．２．２］オクタンビス−（テトラフルオロボラート）、Ａｉｒ Ｐｒｏｄｕｃｔｓ＆Ｃｈｅｍｉｃａｌｓから入手可能）を加えた。反応混合物を１時間撹拌した後、そのままＲＰＬＣにかけて、望ましいモノフルオロ生成物が無色の発泡剤として得られた。ＬＣＭＳ（Ｍ＋Ｎａ）＝６８５．３。
^１Ｈ ＮＭＲ（ＣＤＣｌ_３）：δ７．４４（ｍ、２Ｈ）、７．４から７．１５（ｍ、１０Ｈ）、６．８２（ｂｔ、Ｊ＝８．２Ｈｚ、１Ｈ）、５．３６（ｂｄ、Ｊ＝８．６Ｈｚ、１Ｈ）、５．２３（ｂｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、４．８２（ｔ、Ｊ＝９．５Ｈｚ、１Ｈ）、４．４４（ｄ、Ｊ＝１０．６Ｈｚ、２Ｈ）、３．６１（ｓ、３Ｈ）、３．４０（ｍ、５Ｈ）、３．２１（ｍ、１Ｈ）、３．０２（ｍ、１Ｈ）、１．６０から１．４８（ｍ、２Ｈ）、１．２０から０．９２（ｍ、４Ｈ）、０．７５（ｄ、６Ｈ）、０．７５（ｔ、Ｊ＝７．３Ｈｚ、３Ｈ）、０．５５（ｍ、１Ｈ）、０．２１（ｍ、１Ｈ）。

Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-ethylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- To a solution of 1- (diphenylmethyl) -2-oxoethyl] carbamate (220 mg, 0.33 mmol, Example D2) in 8 mL of MeCN, 117 mg (0.330 mmol) of Selectfluor® (ie, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebis- (tetrafluoroborate), available from Air Products & Chemicals) was added. The reaction mixture was stirred for 1 hour and then directly subjected to RPLC to give the desired monofluoro product as a colorless blowing agent. LCMS (M + Na) = 685.3.
¹ H NMR (CDCl ₃ ): δ 7.44 (m, 2H), 7.4 to 7.15 (m, 10H), 6.82 (bt, J = 8.2 Hz, 1H), 5.36 (bd , J = 8.6 Hz, 1H), 5.23 (bd, J = 8.3 Hz, 1H), 4.82 (t, J = 9.5 Hz, 1H), 4.44 (d, J = 10. 6 Hz, 2H), 3.61 (s, 3H), 3.40 (m, 5H), 3.21 (m, 1H), 3.02 (m, 1H), 1.60 to 1.48 (m) 2H), 1.20 to 0.92 (m, 4H), 0.75 (d, 6H), 0.75 (t, J = 7.3 Hz, 3H), 0.55 (m, 1H), 0.21 (m, 1H).

Example D4
N-{(1S, 5S) -6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl)- L-Phenylalaninamide

手順Ｄ１−４からの（２Ｓ）−６−アミノ−２−［ビス（ｔｅｒｔ−ブトキシカルボニル）アミノ］ヘプタン酸を、手順Ｄ２−３（Ｍｏｃ−２−Ｃｌ−Ｐｈｅ ＨＳＵエステルをＭｏｃ−ジ−Ｐｈｅ−ＨＳＵエステルの代わりに使用）、Ｆ１−１（ＭｅＯＨをＥｔＯＨの代わりに使用）、Ｄ２−５、Ｄ２−６、Ａ２−５、Ａ２−６およびＡ２−７を使用して、Ｎ−｛（１Ｓ，５Ｓ）−６−アミノ−５−［［（４−アミノフェニル）スルホニル］（３−メチルブチル）アミノ］−１−メチルヘキシル｝−２−クロロ−Ｎα−（メトキシカルボニル）−Ｌ−フェニルアラニンアミドを生成した。ＭＳ：Ｍ＋Ｈ＝６１０、６１１（Ｃｌパターン）。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＭｅＯＤ）δ７．５４（ｄ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．３９−３７（ｍ、１Ｈ）、７．２８−７．１７（ｍ、３Ｈ）、６．６５（ｄ、Ｊ＝７．２Ｈｚ、２Ｈ）、４．３４（ｔ、Ｊ＝８．２Ｈｚ、１Ｈ）、３．７２から３．４５（ｍ、５Ｈ）、３．５５（ｓ、３Ｈ）、３．２１（ｄ、Ｊ＝６．３Ｈｚ、１Ｈ）、３．１８（ｄ、Ｊ＝６．３Ｈｚ、１Ｈ）、３．１０から３．０３（ｍ、１Ｈ）、３．９７から３．９２（ｍ、３Ｈ）、１．５８から１．４８（ｍ、３Ｈ）、１．３９から１．３２（ｍ、１Ｈ）、１．１８から１．０３（ｍ、３Ｈ）、０．９７（ｄ、Ｊ＝６．７Ｈｚ、３Ｈ）、０．９２（ｄ、Ｊ＝６．０Ｈｚ、６Ｈ）、０．８６から０．８０（ｍ、２Ｈ）。

(2S) -6-amino-2- [bis (tert-butoxycarbonyl) amino] heptanoic acid from Procedure D1-4, Procedure D2-3 (Moc-2-Cl-Phe HSU ester to Moc-di-Phe -Used instead of HSU ester), F1-1 (MeOH used instead of EtOH), D2-5, D2-6, A2-5, A2-6 and A2-7, N-{( 1S, 5S) -6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl) -L-phenylalaninamide Was generated. MS: M + H = 610, 611 (Cl pattern). ¹ H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.2 Hz, 2H), 7.39-37 (m, 1H), 7.28-7.17 (m, 3H), 6.65 (D, J = 7.2 Hz, 2H), 4.34 (t, J = 8.2 Hz, 1H), 3.72 to 3.45 (m, 5H), 3.55 (s, 3H), 3 .21 (d, J = 6.3 Hz, 1H), 3.18 (d, J = 6.3 Hz, 1H), 3.10 to 3.03 (m, 1H), 3.97 to 3.92 ( m, 3H), 1.58 to 1.48 (m, 3H), 1.39 to 1.32 (m, 1H), 1.18 to 1.03 (m, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.0 Hz, 6H), 0.86 to 0.80 (m, 2H).

The following examples (Table D) are prepared using appropriate procedures (R ⁵ CH ₂ NO _2, ArSO ₂ Cl, R ¹ OH, HO ₂ C—CHR ⁶ —NHR ⁷ or the corresponding hydroxysuccinic acid ester). In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal.

Example E1
Methyl [(1S) -2-({(5S) -5-[[3-fluoro-4-aminophenyl) sulfonyl]-((3S) -3-cyclopropylbutyl) amino] -6-hydroxy-1- Methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate

手順Ｅ１−１：メチルＮ^２，Ｎ^６−ビス（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−リジン酸塩

Procedure E1-1: Methyl N ² , N ⁶ -bis (tert-butoxycarbonyl) -L-lysinate

エプシロン−Ｂｏｃリジンメチルエステル１（３５．９ｇ、１２１ｍｍｏｌ）をＣＨ_２Ｃｌ_２（２５０ｍＬ）に懸濁して室温で撹拌した溶液に、Ｂｏｃ_２Ｏ、９９％（２８．１ｍＬ、１２１ｍｍｏｌ）を加えた後、トリエチルアミン、９９．５％（２０．２３ｍＬ、１４５ｍｍｏｌ）を注意深く加えた。固体を溶解させると、穏やかなガス発生が見られた。１時間後、反応混合物は、透明な浅黄色で認められるガス発生はなかった。一定分量をＮ_２下で濃縮した。反応混合物を、室温で夜通し放置した。分液漏斗に移し、水（２×２５０ｍＬ）、ＮａＨＣＯ_３（５０ｍＬ ５０％飽和化）、およびブラインで洗浄した。ＭｇＳＯ_４で乾燥させ、濾過し、濃縮すると、灰色がかった白色の固体（ｗｔ ４２ｇ）が得られる。ＭＳ：Ｍ＋Ｎａ＝３８３。

After adding Boc ₂ O, 99% (28.1 mL, 121 mmol) to a solution of epsilon-Boc lysine methyl ester 1 (35.9 g, 121 mmol) suspended in CH ₂ Cl ₂ (250 mL) and stirred at room temperature. , Triethylamine, 99.5% (20.23 mL, 145 mmol) was carefully added. Mild gas evolution was seen as the solid dissolved. After 1 hour, the reaction mixture was clear and pale yellow with no gas evolution observed. Aliquots were concentrated under N _2. The reaction mixture was left overnight at room temperature. Transfer to separatory funnel and wash with water (2 × 250 mL), NaHCO ₃ (50 mL 50% saturated), and brine. Dry over MgSO ₄ , filter and concentrate to give an off-white solid (wt 42 g). MS: M + Na = 383.

Procedure E1-2: Bis-Boc-ricinol

メチルＮ^２、Ｎ^６−ビス（ｔｅｒｔ−ブトキシカルボニル）−Ｌ−リジン酸塩（２３５ｇ、６５２ｍｍｏｌ）をＴＨＦ（２０００ｍＬ）に入れ、氷／水槽で１０℃に冷却した溶液に、水素化ホウ素リチウム（＞９０％（２２ｇ、１０１０ｍｍｏｌ））を、４５分間にわたり何回かに分けて加えた。付加が完了した後、反応混合物を２０分間寝かした後、５０℃まで１時間温めた。反応混合物を０℃まで冷まし、ＭｅＯＨ（５０ｍＬ）を滴下して加えて急冷した。１５分後、０℃で槽を除去し、５０ｍＬの５Ｎ ＮａＯＨを２５０ｍＬのブラインとともに加えた。室温で３０分間撹拌した後、反応混合物を５００ｍＬの水で希釈し、分割した。水層を塩が溶解するまで、より多量の水で希釈した後、エーテル（５００ｍＬ）で１回抽出した。混合有機質層をＮａ_２ＳＯ_４上で乾燥させた。酢酸エチルを加え、混合物を室温で１５分間撹拌し、濾過し、濃縮させて、無色の粘性の油が得られた。ＭＳ：Ｍ＋Ｎａ＝３５５。

Methyl N ² , N ⁶ -bis (tert-butoxycarbonyl) -L-lysinate (235 g, 652 mmol) in THF (2000 mL) and cooled to 10 ° C. in an ice / water bath was added to lithium borohydride ( > 90% (22 g, 1010 mmol)) was added in several portions over 45 minutes. After the addition was complete, the reaction mixture was aged for 20 minutes and then warmed to 50 ° C. for 1 hour. The reaction mixture was cooled to 0 ° C. and quenched by the dropwise addition of MeOH (50 mL). After 15 minutes, the bath was removed at 0 ° C. and 50 mL of 5N NaOH was added along with 250 mL of brine. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with 500 mL of water and partitioned. The aqueous layer was diluted with more water until the salt dissolved and then extracted once with ether (500 mL). The combined organic layer was dried over Na ₂ SO ₄ . Ethyl acetate was added and the mixture was stirred at room temperature for 15 minutes, filtered and concentrated to give a colorless viscous oil. MS: M + Na = 355.

Procedure E1-3: Bis-Boc-ricinol TBS-ether

ビス−Ｂｏｃ−リシノール（２１５ｇ、６４７ｍｍｏｌ）をＣＨ_２Ｃｌ_２（２５００ｍＬ）に入れた溶液に、イミダゾール（＞９９％（８６ｇ、１２６３ｍｍｏｌ））を加えた後、ＴＢＳ−Ｃｌ、９７％（１０７ｇ、７１１ｍｍｏｌ）を数分間にわたり何回かに分けて加え、その間、内部温度を３０℃以下に保った。反応混合物を２日間にわたり夜通し撹拌した。次に、２０ｇのイミダゾールおよび２０ｇのＴＢＳＣｌを加え、反応混合物を３時間寝かした後、２０ｇのイミダゾール、２０ｇのＴＢＳＣｌおよび１ｇのＤＭＡＰを加え、反応混合物を３５℃で３時間撹拌した。反応混合物を分液漏斗に移し、２Ｎ ＨＣｌ（２×５００ｍＬ）およびブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、濾過し、濃縮させて、無色の粘性の油が得られた。ＭＳ：Ｍ＋Ｎａ＝４６９。

To a solution of bis-Boc-ricinol (215 g, 647 mmol) in CH ₂ Cl ₂ (2500 mL) was added imidazole (> 99% (86 g, 1263 mmol)) followed by TBS-Cl, 97% (107 g, 711 mmol). ) Was added in several portions over several minutes, while maintaining the internal temperature below 30 ° C. The reaction mixture was stirred overnight for 2 days. Next, 20 g imidazole and 20 g TBSCl were added and the reaction mixture was aged for 3 hours, then 20 g imidazole, 20 g TBSCl and 1 g DMAP were added and the reaction mixture was stirred at 35 ° C. for 3 hours. The reaction mixture was transferred to a separatory funnel and washed with 2N HCl (2 × 500 mL) and brine, dried over MgSO ₄ , filtered and concentrated to give a colorless viscous oil. MS: M + Na = 469.

Procedure E1-4: N-Boc tert-butyl ((5S) -5-amino-6-{[tert-butyl (dimethyl) silyl] oxy} hexanoyl) carbamate

ビス−Ｂｏｃ−リシノールＴＢＳ−エーテル１（２８９ｇ、６４７ｍｍｏｌ）をＥｔＯＡｃ（１０００ｍＬ）に入れた溶液に、水（１４００ｍＬ）および酸化ルテニウム（ＩＶ）水和物（４．３ｇ、２８．５ｍｍｏｌ）を加えた。次に、１００ｇの臭素酸ナトリウムを加え、反応混合物を４０から４５℃で５時間撹拌し、セライトで濾過し、分割して酢酸エチルで抽出した。混合有機質層を重亜硫酸ナトリウム水溶液で洗浄した後、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥し、木炭（Ｄａｒｃｏ Ｇ−６０）で処理し、漏斗内の約２インチのシリカを通過させて濾過し、濃いスラリーに濃縮した。少量のヘキサンを加え、混合物を０℃まで冷却し、濾過した。濾塊を１：１ ＥｔＯＡｃ／ヘキサンで、次にヘキサンで洗浄した後、白色の固体に乾燥させたが、これは、望ましい生成物ではなかった。ろ液を濃縮した後、ヘキサンで希釈し、再び濾過した。ろ液を１５００ｇカラム上にポンプで注入し、ヘプタンで平衡化した後、１カラム用量のヘプタンで、次に勾配を５０％にして溶出した。第一のカラム容量は収集せず、４５０ｍＬ部分を収集した。適切な部分を濃縮して、次の無色の油が得られた。Ｎ−Ｂｏｃ ｔｅｒｔ−ブチル（（５Ｓ）−５−アミノ−６−｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝ヘキサノイル）カルバミン酸塩。ＭＳ：Ｍ＋Ｎａ＝４８３。

To a solution of bis-Boc-ricinol TBS-ether 1 (289 g, 647 mmol) in EtOAc (1000 mL) was added water (1400 mL) and ruthenium (IV) oxide hydrate (4.3 g, 28.5 mmol). . Next, 100 g of sodium bromate was added and the reaction mixture was stirred at 40-45 ° C. for 5 hours, filtered through celite, divided and extracted with ethyl acetate. The combined organic layers are washed with aqueous sodium bisulfite, then with brine, dried over MgSO ₄ , treated with charcoal (Darco G-60), filtered through approximately 2 inches of silica in a funnel. And concentrated to a thick slurry. A small amount of hexane was added and the mixture was cooled to 0 ° C. and filtered. The filter cake was washed with 1: 1 EtOAc / hexane and then with hexane and then dried to a white solid, which was not the desired product. The filtrate was concentrated, diluted with hexane and filtered again. The filtrate was pumped onto a 1500 g column, equilibrated with heptane, and then eluted with one column dose of heptane and then a gradient of 50%. The first column volume was not collected and a 450 mL portion was collected. The appropriate portion was concentrated to give the next colorless oil. N-Boc tert-butyl ((5S) -5-amino-6-{[tert-butyl (dimethyl) silyl] oxy} hexanoyl) carbamate. MS: M + Na = 483.

Procedure E1-5: tert-butyl [(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-hydroxypentyl] carbamate

Ｎ−Ｂｏｃ ｔｅｒｔ−ブチル（（５Ｓ）−５−アミノ−６−｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝ヘキサノイル）カルバミン酸塩（４７ｇ、１０２ｍｍｏｌ）を２−プロパノール（９００ｍＬ）および水（９０ｍＬ）に入れた溶液に、水素化ホウ素ナトリウム９８＋％（４．７ｇ、１２４ｍｍｏｌ）を加え、反応混合物を室温で週末を通して撹拌し、濃縮し、酢酸エチルおよび１００ｍＬの１ Ｎ ＮａＯＨで希釈し、分割し、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、濾過し、濃縮させて、油性の固体が得られた。残留物を少量のＥｔＯＡｃを含むヘキサンで希釈し、濾過して、ヘキサンで洗浄した。ろ液を７５０ｇカラム上にポンプで注入し、ヘプタンで平衡化した後、１カラム用量のヘプタンで、次に勾配を５０％ＥｔＯＡｃ／ヘプタンにして溶出した。適切な部分を油性の固体に濃縮し、高真空下で乾燥させて昇華する固体にしたが、これは望ましい生成物ではなかった。固体をヘキサンで希釈し、混合物を０℃まで冷却し、望ましい生成物の結晶化を誘発させた。ＭＳ：Ｍ＋Ｎａ＝３７０、Ｍ−Ｂｏｃ＋１＝２４８。

N-Boc tert-butyl ((5S) -5-amino-6-{[tert-butyl (dimethyl) silyl] oxy} hexanoyl) carbamate (47 g, 102 mmol) in 2-propanol (900 mL) and water (90 mL) ) Was added sodium borohydride 98 +% (4.7 g, 124 mmol) and the reaction mixture was stirred at room temperature over the weekend, concentrated, diluted with ethyl acetate and 100 mL of 1 N NaOH and partitioned. , Washed with brine, dried over MgSO ₄ , filtered and concentrated to give an oily solid. The residue was diluted with hexane containing a small amount of EtOAc, filtered and washed with hexane. The filtrate was pumped onto a 750 g column, equilibrated with heptane, and then eluted with one column dose of heptane and then with a gradient of 50% EtOAc / heptane. The appropriate portion was concentrated to an oily solid and dried under high vacuum to a sublimated solid, which was not the desired product. The solid was diluted with hexane and the mixture was cooled to 0 ° C. to induce crystallization of the desired product. MS: M + Na = 370, M-Boc + 1 = 248.

Procedure E1-6 (5S) -5-[(tert-butoxycarbonyl) amino] -6-{[tert-butyl (dimethyl) silyl] oxy} pivalate hexyl

ｔｅｒｔ−ブチル［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−５−ヒドロキシペンチル］カルバミン酸塩（２．５ｇ、７．１９ｍｍｏｌ）を３６ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、ピリジン（１．１０ｍＬ、１３．６７ｍｍｏｌ）および塩化ピバロイル（１．６０ｍＬ、１２．９５ｍｍｏｌ）を加えた。室温で２時間撹拌した後、さらに分割量のピリジン（０．５５ｍＬ、６．８３ｍｍｏｌ）および塩化ピバロイル（０．８０ｍＬ、６．４７ｍｍｏｌ）を加えた。反応混合物を、さらに１時間後にＥｔＯＡｃで希釈することで急冷した。有機物を０．５Ｍ ＫＨＳＯ_４、飽和ＮａＨＣＯ_３水溶液およびブラインの順で洗浄した後、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（０−＞１５％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい化合物が粘性の油として得られた。

tert-Butyl [(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-hydroxypentyl] carbamate (2.5 g, 7.19 mmol) in 36 mL CH ₂ Cl ₂ To the charged solution was added pyridine (1.10 mL, 13.67 mmol) and pivaloyl chloride (1.60 mL, 12.95 mmol). After stirring at room temperature for 2 hours, additional portions of pyridine (0.55 mL, 6.83 mmol) and pivaloyl chloride (0.80 mL, 6.47 mmol) were added. The reaction mixture was quenched after another hour by diluting with EtOAc. The organics were washed sequentially with 0.5M KHSO ₄ , saturated aqueous NaHCO ₃ solution and brine, then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (0-> 15% EtOAc / hexanes) to give the desired compound as a viscous oil.

Procedure E1-7 (5S) -5-[(-butoxycarbonyl) (3-methylbutyl) amino] -6-{[tert-butyl (dimethyl) silyl] oxy} hexyl pivalate

（５Ｓ）−５−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−｛［ｔｅｒｔブチル（ジメチル）シリル］オキシ｝ピバル酸ヘキシル（２．８５ｇ、６．６０ｍｍｏｌ）を３３ｍＬのＤＭＦに入れた溶液に、ＮａＨ（９５％、０．３３４ｇ、１２．２ｍｍｏｌ）を加えた。室温で３０分後、１−ヨード−３−メチルブタン（２．６３ｍＬ、１９．８１ｍｍｏｌ）を加え、反応混合物を５０℃で３時間加熱した。次に、反応混合物を室温まで冷まし、飽和ＮＨ_４Ｃｌ水溶液を加えて急冷させ、ＥｔＯＡｃおよびＨ_２Ｏで希釈した。層を分離し、および有機物を３Ｍ ＬｉＣｌ（３ｘ）およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（０−＞１５％ＥｔＯＡｃ／ヘキサン）により精製し、２．３９ｇの望ましい化合物が粘性の油として得られた。

To a solution of (5S) -5-[(tert-butoxycarbonyl) amino] -6-{[tertbutyl (dimethyl) silyl] oxy} pivalate hexyl (2.85 g, 6.60 mmol) in 33 mL DMF. , NaH (95%, 0.334 g, 12.2 mmol) was added. After 30 minutes at room temperature, 1-iodo-3-methylbutane (2.63 mL, 19.81 mmol) was added and the reaction mixture was heated at 50 ° C. for 3 hours. The reaction mixture was then cooled to room temperature, quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc and H ₂ O. The layers were separated, and the organics were washed with 3M LiCl (3x) and brine, dried over _Na 2 SO _4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-> 15% EtOAc / hexane) to give 2.39 g of the desired compound as a viscous oil.

Procedure E1-8 [(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-hydroxypentyl] (3-methylbutyl) carbamate

（５Ｓ）−５−［（−ブトキシカルボニル）（３−メチルブチル）アミノ］−６−｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝ピバル酸ヘキシル（２．２９ｇ、４．５６ｍｍｏｌ）を２３ｍＬのＴＨＦに入れた溶液に、ＬｉＢＨ_４（ＴＨＦ中２Ｍ、９．１３ｍＬ、１８．２５ｍｍｏｌ）を加えた。混合物を５０℃で３時間加熱し、その後、さらに分割量のＬｉＢＨ_４（ＴＨＦ中２Ｍ、４．６ｍＬ、９．１ｍｍｏｌ）を加え、反応混合物を５０℃でさらに１時間加熱した。次に、反応混合物を室温まで冷まし、ＥｔＯＡｃ、次に飽和ＮＨ_４Ｃｌ水溶液を加えて急冷した。次に、急冷した混合物をＥｔＯＡｃで希釈し、および有機物をＨ_２Ｏおよびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。残留物をシリカゲルクロマトグラフィー（１０−＞４５％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい化合物が粘性の油として得られた。

(5S) -5-[(-Butoxycarbonyl) (3-methylbutyl) amino] -6-{[tert-butyl (dimethyl) silyl] oxy} pivalate hexyl (2.29 g, 4.56 mmol) in 23 mL THF To the solution in was added LiBH ₄ (2M in THF, 9.13 mL, 18.25 mmol). The mixture was heated at 50 ° C. for 3 hours, after which a further portion of LiBH ₄ (2M in THF, 4.6 mL, 9.1 mmol) was added and the reaction mixture was heated at 50 ° C. for an additional hour. The reaction mixture was then cooled to room temperature and quenched by the addition of EtOAc followed by saturated aqueous NH ₄ Cl. The quenched mixture was then diluted with EtOAc and the organics were washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (10-> 45% EtOAc / hexanes) to give the desired compound as a viscous oil.

Procedure E1-9 [(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-oxopentyl] (3-methylbutyl) carbamate

［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−５−ヒドロキシペンチル］（３−メチルブチル）カルバミン酸塩（１．０５ｇ、２．５１ｍｍｏｌ）を１７ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、Ｎ−メチルモルホリンＮ−酸化物（０．３８３ｇ、３．２７ｍｍｏｌ）および活性４Ａ分子ふるい（１．０５ｇ）を加えた。１０分後、ＴＰＡＰ（０．０４４ｇ、０．１２６ｍｍｏｌ）を一度に加えた。４５分後、反応混合物をシリカゲルクロマトグラフィー（０−＞２５％ＥｔＯＡｃ／ヘキサン）で精製し、０．８９ｇの望ましい生成物が得られた。

[(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-hydroxypentyl] (3-methylbutyl) carbamate (1.05 g, 2.51 mmol) in 17 mL CH ₂ Cl _To the solution in ₂ was added N-methylmorpholine N-oxide (0.383 g, 3.27 mmol) and active 4A molecular sieve (1.05 g). After 10 minutes, TPAP (0.044 g, 0.126 mmol) was added in one portion. After 45 minutes, the reaction mixture was purified by silica gel chromatography (0-> 25% EtOAc / hexanes) to give 0.89 g of the desired product.

Procedure E1-10 tert-butyl ((1S, 5E) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-{[(R-tert-butylsulfinyl] imino} pentyl) (3 -Methylbutyl) carbamate

［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−５−オキソペンチル］（３−メチルブチル）カルバミン酸塩（０．８９０ｇ、２．１４ｍｍｏｌ）を１４ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、ＭｇＳＯ_４（１．２９ｇ、１０．７１ｍｍｏｌ）、ＰＰＴＳ（０．０５４ｇ、０．２１４ｍｍｏｌ）および（Ｒ）−ｔｅｒｔブタンスルフィンアミド（０．３３７ｇ、２．７８ｍｍｏｌ）をその順序で加えた。１６時間後、反応混合物をセライトのパッドを通過させて濾過し、新鮮なＣＨ_２Ｃｌ_２で濯いだ。濾過物をシリカゲルクロマトグラフィー（１０−＞４５％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい生成物が粘性の油として得られた。

[(1S) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-oxopentyl] (3-methylbutyl) carbamate (0.890 g, 2.14 mmol) in 14 mL CH ₂ Cl _To the solution in ₂ was added MgSO ₄ (1.29 g, 10.71 mmol), PPTS (0.054 g, 0.214 mmol) and (R) -tertbutanesulfinamide (0.337 g, 2.78 mmol) in that order. Added in. After 16 hours, the reaction mixture was filtered through a pad of celite and rinsed with fresh CH ₂ Cl ₂ . The filtrate was purified by silica gel chromatography (10-> 45% EtOAc / hexanes) to give the desired product as a viscous oil.

Procedure E1-11 tert-butyl ((1S, 5R) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-{[(R-tert-butylsulfinyl] amino} -5-cyclo Propylpentyl) (3-methylbutyl) carbamate

ｔｅｒｔ−ブチル（（１Ｓ，５Ｅ）−１−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−５−｛［（Ｒ−ｔｅｒｔ−ブチルスルフィニル］イミノ｝ペンチル）（３−メチルブチル）カルバミン酸塩（０．２６８ｇ、０．５１７ｍｍｏｌ）を５．１ｍＬヘキサンに−１０℃で入れた溶液に、シクロプロピルマグネシウム臭化物（ＴＨＦ中０．５Ｍ、１．５５ｍＬ、０．７７５ｍｍｏｌ）を加えた。３時間後、バッチを３℃以下まで温め、その時点で反応混合物を飽和ＮＨ_４Ｃｌ水溶液およびＥｔＯＡｃを加えて急冷した。層を分離し、および有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濾過物をシリカゲルクロマトグラフィー（２５−＞７５％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい生成物が粘性の油として得られた。

tert-butyl ((1S, 5E) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-{[(R-tert-butylsulfinyl] imino} pentyl) (3-methylbutyl) carbamine To a solution of the acid salt (0.268 g, 0.517 mmol) in 5.1 mL hexane at −10 ° C. was added cyclopropylmagnesium bromide (0.5 M in THF, 1.55 mL, 0.775 mmol). After time, the batch was warmed to below 3 ° C., at which point the reaction mixture was quenched by adding saturated aqueous NH ₄ Cl and EtOAc, the layers were separated and the organics were washed with brine and dried over Na ₂ SO _4. The filtrate was purified by silica gel chromatography (25-> 75% EtOAc / hexanes), Masui product was obtained as a viscous oil.

Procedure E1-12 tert-Butyl ((1S, 5R) -5-amino-1- (hydroxymethyl) -5-cyclopropylpentyl) (3-methylbutyl) carbamate hydrochloride

ｔｅｒｔ−ブチル（（１Ｓ，５Ｒ）−１−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−５−｛［（Ｒ−ｔｅｒｔ−ブチルスルフィニル］アミノ｝−５−シクロプロピルペンチル）（３−メチルブチル）カルバミン酸塩（４４０ｍｇ、０．７８４ｍｍｏｌ）を、０℃で維持した７．８ｍＬ ＭｅＯＨに入れた溶液に、ＨＣｌをＥｔ_２Ｏ（１Ｍ、１．５７ｍＬ、１．５７ｍｍｏｌ）に入れたものを加えた。１時間後、槽を除去し、反応混合物を室温で２時間進行させた。次に反応混合物を濃縮させて、望ましい生成物が白色の固体として得られた。ＭＳ：Ｍ＋Ｈ＝３４３。Ｍ−Ｂｏｃ＋１＝２４３。

tert-butyl ((1S, 5R) -1-({[tert-butyl (dimethyl) silyl] oxy} methyl) -5-{[(R-tert-butylsulfinyl] amino} -5-cyclopropylpentyl) ( To a solution of 3-methylbutyl) carbamate (440 mg, 0.784 mmol) in 7.8 mL MeOH maintained at 0 ° C., HCl was added to Et ₂ O (1M, 1.57 mL, 1.57 mmol). After 1 hour, the bath was removed and the reaction mixture was allowed to proceed for 2 hours at room temperature, then the reaction mixture was concentrated to give the desired product as a white solid, MS: M + H = 343. M-Boc + 1 = 243.

Procedure E1-13 Methyl [1S 2-[((1R, 5S) -5-[(tert-butoxycarbonyl) (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} amino) -1- ( Diphenylmethyl) -2-oxoethyl] carbamate

ｔｅｒｔ−ブチル（（１Ｓ，５Ｒ）−５−アミノ−１−（ヒドロキシメチル）−５−シクロプロピルペンチル）（３−メチルブチル）カルバミン酸塩塩酸塩（３７１ｍｇ、０．９７９ｍｍｏｌ）および２Ｓ−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパン酸（３２２ｍｇ、１．０７７ｍｍｏｌ）を９．８ｍＬ ＤＭＦに入れた溶液に、ジイソプロピルエチルアミン（０．１７０ｍＬ、０．９７９ｍｍｏｌ）、ＥＤＣ（２６３ｍｇ、１．３７ｍｍｏｌ）およびＨＯＡｔ（１３．３ｍｇ、０．０９８ｍｍｏｌ）を加えた。室温で１６時間攪拌した後、反応混合物をＥｔＯＡｃで希釈し、有機物を０．５Ｍ ＫＨＳＯ_４、１Ｈ ＮａＯＨ、３Ｍ ＬｉＣｌ（３ｘ）およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濾過物をシリカゲルクロマトグラフィー（３０−＞８％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい生成物が白色の固体として得られた。ＭＳ：Ｍ＋Ｈ＝６２４、Ｍ−Ｂｏｃ＋Ｈ＝５２４。

tert-Butyl ((1S, 5R) -5-amino-1- (hydroxymethyl) -5-cyclopropylpentyl) (3-methylbutyl) carbamate hydrochloride (371 mg, 0.979 mmol) and 2S-2- [ To a solution of (methoxycarbonyl) amino] -3,3-diphenylpropanoic acid (322 mg, 1.077 mmol) in 9.8 mL DMF was added diisopropylethylamine (0.170 mL, 0.979 mmol), EDC (263 mg, 1. 37 mmol) and HOAt (13.3 mg, 0.098 mmol) were added. After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc and the organics were washed with 0.5M KHSO ₄ , 1H NaOH, 3M LiCl (3 ×) and brine, dried over Na ₂ SO ₄ , filtered, Concentrated. The filtrate was purified by silica gel chromatography (30-> 8% EtOAc / hexanes) to give the desired product as a white solid. MS: M + H = 624, M-Boc + H = 524.

Procedure E1-14 Methyl [1S-2-[((1R, 5S)-)-1-cyclopropyl-6-hydroxy-5-[(3-methylbutyl) amino] hexyl} amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate

メチル［１Ｓ ２−［（（１Ｒ、５Ｓ）−５−［（ｔｅｒｔ−ブトキシカルボニル）（３−メチルブチル）アミノ］−１−シクロプロピル−６−ヒドロキシヘキシル｝アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩の溶液に、７．１ｍＬの４Ｍ ＨＣｌをジオキサンに入れたものを加えた。室温で４時間攪拌した後、反応混合物を濃縮させて、望ましい生成物（４０６ｍｇ）が白色の固体として得られた。ＭＳ：Ｍ＋Ｈ＝５２４。

Methyl [1S 2-[((1R, 5S) -5-[(tert-butoxycarbonyl) (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} amino) -1- (diphenylmethyl)- To a solution of 2-oxoethyl] carbamate was added 7.1 mL of 4M HCl in dioxane. After stirring at room temperature for 4 hours, the reaction mixture was concentrated to give the desired product (406 mg) as a white solid. MS: M + H = 524.

Procedure E1-15 Methyl [1S-2-[((1R, 5S) -1-cyclopropyl-6-hydroxy-5-{(3-methylbutyl) [(4-nitrophenyl) sulfonyl] amino} hexyl) amino] -1- (Diphenylmethyl) -2-oxoethyl] carbamate

メチル［１Ｓ−２−［（（１Ｒ，５Ｓ）−）−１−シクロプロピル−６−ヒドロキシ−５−［（３−メチルブチル）アミノ］ヘキシル｝アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩塩酸塩（２０３ｍｇ、０．３６２ｍｍｏｌ）およびジイソプロピルエチルアミン（０．１３３ｍＬ、０．７６１ｍｍｏｌ）を２．４ｍＬ ＣＨ_２Ｃｌ_２に入れたスラリーに、４−塩化ニトロフェニルスルホニル（８４ｍｇ、０．３８１ｍｍｏｌ）を加えた。室温で１６時間攪拌した後、さらに一回の分割量の４−塩化ニトロフェニルスルホニル（３５ｍｇ、０．１５８ｍｍｏｌ）を加え、さらに３．５時間後、反応混合物をＥｔＯＡｃで希釈し、有機物を飽和ＮａＨＣＯ_３水溶液およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濾過物をシリカゲルクロマトグラフィー（３０−＞８％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい生成物が白色の固体として得られた。ＭＳ：Ｍ＋Ｈ＝７０９。

Methyl [1S-2-[((1R, 5S)-)-1-cyclopropyl-6-hydroxy-5-[(3-methylbutyl) amino] hexyl} amino) -1- (diphenylmethyl) -2-oxoethyl ] carbamate hydrochloride (203 mg, 0.362 mmol) and diisopropylethylamine (0.133 mL, 0.761 mmol) to a slurry placed in 2.4mL _{CH 2} Cl 2, 4- chloride nitrophenyl sulfonyl (84 mg, 0. 381 mmol) was added. After stirring at room temperature for 16 hours, a further portion of 4-nitrophenylsulfonyl chloride (35 mg, 0.158 mmol) was added and after another 3.5 hours the reaction mixture was diluted with EtOAc and the organics were saturated NaHCO 3. Washed with ₃ aqueous solutions and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The filtrate was purified by silica gel chromatography (30-> 8% EtOAc / hexanes) to give the desired product as a white solid. MS: M + H = 709.

Procedure E-16 Methyl [1S-2-[((1R, 5S) -1-cyclopropyl-6-hydroxy-5-{(3-methylbutyl) [(4-aminophenyl) sulfonyl] amino} hexyl) amino] -1- (Diphenylmethyl) -2-oxoethyl] carbamate Methyl [1S-2-[((1R, 5S) -1-cyclopropyl-6-hydroxy-5-{(3-methylbutyl) [(4- To a solution of nitrophenyl) sulfonyl] amino} hexyl) amino] -1- (diphenylmethyl) -2-oxoethyl] carbamate (102 mg, 0.144 mmol) in 0.72 mL EtOH and 0.72 mL THF was added SnCl. ₂ (136 mg, 0.719 mmol) was added. The reaction mixture was placed in an oil bath preheated to 85 ° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and quenched by adding saturated aqueous NaHCO ₃ solution. The quenched reaction mixture was diluted with EtOAc and H ₂ O and the layers were separated. After washing the aqueous layer with EtOAc (4 ×), the combined organics were dried over Na ₂ SO ₄ , filtered through a pad of celite, and concentrated. The filtrate was purified by silica gel chromatography (40-> 100% EtOAc / hexanes) to give the desired product as a white blowing agent. MS: M + H = 679. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.6 Hz, 2H), 7.30 to 7.18 (m, 5H), 6.69 (d, J = 8.6 Hz, 1H ), 5.47 (d, J = 8.2 Hz, 1H), 5.10 (d, J = 8.2 Hz, 1H), 4.78 (t, J = 9.7 Hz, 1H), 4.49 (D, J = 10.1 Hz, 1H), 4.40 (s, 2H), 3.61 (s, 3H), 3.48 to 3.47 (m, 3H), 3.17 (ddd, J = 15.0 Hz, 9.6 Hz, 5.3 Hz, 1H), 3.05 to 2.95 (m, 2H), 2.47 (s, 1H), 1.56 to 1.48 (m, 5H) 1.14 (m, 1H), 0.99 (m, 3H), 0.90 (d, J = 1.7 Hz, 3H), 0.88 (d, J = 2.1 Hz, 3H), 0 . 1 (m, 1H), 0.48 to 0.29 (m, 3H), 0.161 (ddd, J = 9.3, 4.6, 4.6 Hz, 1H), 0.045 (m, 1H ).

Example E2
N-{(1R, 5S) -1-cyclopropyl-5-[{[3-fluoro-4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -6-hydroxyhexyl} -4-fluoro -Β- (4-Fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide

手順Ｅ２−１：Ｎ−｛（１Ｒ，５Ｓ）−５−［［（４−ブロモ−３−フルオロフェニル）スルホニル］（３−メチルブチル）アミノ］−１−シクロプロピル−６−ヒドロキシヘキシル｝−４−フルオロ−β−（４−フルオロフェニル）−Ｎα−（メトキシカルボニル）−Ｌ−フェニルアラニンアミド

Procedure E2-1: N-{(1R, 5S) -5-[[(4-Bromo-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -4 -Fluoro-β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide

Ｎ−｛（１Ｒ，５Ｓ）−５−［［（４−ブロモ−３−フルオロフェニル）スルホニル］（３−メチルブチル）アミノ］−１−シクロプロピル−６−ヒドロキシヘキシル｝−４−フルオロ−β−（４−フルオロフェニル）−Ｎα−（メトキシカルボニル）−Ｌ−フェニルアラニンアミドを、３−フルオロ−４−ブロモ−ベンゼン塩化スルホニルから、実施例Ｅ１の調製で説明したものと類似した手順を使用して調製した。

N-{(1R, 5S) -5-[[(4-Bromo-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -4-fluoro-β- (4-Fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide is obtained from 3-fluoro-4-bromo-benzenesulfonyl chloride using a procedure similar to that described in the preparation of Example E1. Prepared.

Procedure E2-2: Methyl 4-{[[(1S, 5R) -5-cyclopropyl-5-{[4-fluoro-β- (4-fluorophenyl) -N- (methoxycarbonyl) -L-phenylara Nyl] amino} -1- (hydroxymethyl) pentyl] (3-methylbutyl) amino] sulfonyl} -2-fluorobenzoate

Ｎ−｛（１Ｒ，５Ｓ）−５−［［（４−ブロモ−３−フルオロフェニル）スルホニル］（３−メチルブチル）アミノ］−１−シクロプロピル−６−ヒドロキシヘキシル｝−４−フルオロ−β−（４−フルオロフェニル）−Ｎα−（メトキシカルボニル）−Ｌ−フェニルアラニンアミド（４０ｍｇ、０．０５ｍｍｏｌ）を、ＤＭＳＯ：ＭｅＯＨ（１．５ｍＬ）の１：２溶液で溶解し、溶液をアルゴンで浄化した。トリエチルアミン（２０ｍｇ、０．２０ｍｍｏｌ）、酢酸パラジウム（２．２５ｍｇ、１０μｍｏｌ）、１，３−ビス（ジフェニルホスフィノ）プロパン（４．１ｍｇ、１０μｍｏｌ）を、攪拌溶液に加えた。一酸化炭素をバルーンにより導入し、その結果できる装置を空気冷却器に取り付け、８０℃まで１６時間加熱した。次に、粗製の反応混合物をセライト上で濾過し、ブラインおよび酢酸エチル間で分割した。混合有機物を硫酸ナトリウム上で乾燥させ、真空内で濃縮させた。粗製の混合物を、逆相クロマトグラフィーを使用して精製した。適切な部分を酢酸エチル中に抽出し、飽和重炭酸ナトリウムおよびブラインで洗浄し、表題の生成物が透明な油として得られた。ＬＣＭＳ（Ｍ＋１）＝７７６。

N-{(1R, 5S) -5-[[(4-Bromo-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -4-fluoro-β- (4-Fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide (40 mg, 0.05 mmol) was dissolved in a 1: 2 solution of DMSO: MeOH (1.5 mL) and the solution was purged with argon. . Triethylamine (20 mg, 0.20 mmol), palladium acetate (2.25 mg, 10 μmol), 1,3-bis (diphenylphosphino) propane (4.1 mg, 10 μmol) were added to the stirred solution. Carbon monoxide was introduced by balloon and the resulting device was attached to an air cooler and heated to 80 ° C. for 16 hours. The crude reaction mixture was then filtered over celite and partitioned between brine and ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified using reverse phase chromatography. The appropriate portion was extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to give the title product as a clear oil. LCMS (M + 1) = 776.

Procedure E2-3: N-{(1R, 5S) -1-cyclopropyl-5-[{[3-fluoro-4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -6-hydroxyhexyl } -4-Fluoro-β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide methyl 4-{[[(1S, 5R) -5-cyclopropyl-5-{[4-fluoro -Β- (4-Fluorophenyl) -N- (methoxycarbonyl) -L-phenylalanyl] amino} -1- (hydroxymethyl) pentyl] (3-methylbutyl) amino] sulfonyl} -2-fluorobenzoate (4 mg, 5.16 μmol) was dissolved in THF (100 μL), and lithium borohydride (0.11 mg, 5.2 μmol) was added dropwise to the stirring solution. Added. The reaction was stirred for 8 hours before being quenched with saturated ammonium chloride solution, extracted into ethyl acetate, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified using reverse phase chromatography. Appropriate portions were extracted into ethyl acetate and washed with saturated sodium bicarbonate and brine to give the desired product. ¹ H NMR (CDCl ₃ ): δ 7.6 (m, 3H), 7.25 (m, 5H), 7.1 to 6.9 (m, 5H), 5.15 (m, 1H), 5. 05 (m, 1H), 4.8 (m, 2H), 4.4 (m, 1H), 3.7 (s, 3H), 3.6 to 3.4 (m, 2H), 3.25 To 3.05 (m, 2H), 2.8 (m, 1H), 1.7 to 1.5 (m, 4H), 1.35 to 1.25 (m, 4H), 1.0 to 0 0.8 (m, 8H), 0.55 to 0.35 (m, 2H), 0.15 to 0.25 (m, 2H). LCMS (M + 1) = 748.

Example E3
N-{(1R, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide

表題の生成物を、メチル［（１Ｓ）−２−（｛（５Ｓ）−５−［［３−フルオロ−４−アミノフェニル）スルホニル］−（（３Ｓ）−３−シクロプロピルブチル）アミノ］−６−ヒドロキシ−１−メチルヘキシル）アミノ）−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩（実施例Ｅ１）から、実施例Ｄ３で説明した方法のフッ素付加により調製した。ＭＳ Ｍ＋１＝６９７。

The title product is methyl [(1S) -2-({(5S) -5-[[3-fluoro-4-aminophenyl) sulfonyl]-((3S) -3-cyclopropylbutyl) amino]-. 6-hydroxy-1-methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate (Example E1) was prepared by fluorination of the method described in Example D3. MS M + 1 = 697.

The following examples (Table E) show the appropriate building blocks (R ⁵ MgX _, ArSO ₂ Cl, R ¹ X, HO ₂ C using procedures similar to those described in the preparation of Examples E1 to E3. -CHR ⁶ -NHR ⁷ or the corresponding hydroxysuccinic acid ester). In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal.

Example F1
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide

手順Ｆ１−１ エチル（２Ｓ）−２−アミノ−４−ペンテン酸塩塩酸塩
（２Ｓ）−２−アミノペネン酸（１０．５ｇ、９１ｍｍｏｌ）を０℃の１００ｍＬ ＥｔＯＨに入れた溶液に、塩化チオニル（２０．０ｍＬ、２７４ｍｍｏｌ）を３０分間にわたり滴下して加えた。槽を除去し、反応を室温で１６時間にわたり進行させた。反応混合物を濃縮し、褐色がかった残留物をＥｔ_２Ｏ（２ｘ）で滴定して、望ましい生成物が白色の固体として得られた。ＭＳ：Ｍ＋Ｈ＝１４４。

Procedure F1-1 Ethyl (2S) -2-amino-4-pentenoic acid hydrochloride (2S) -2-Aminopenenoic acid (10.5 g, 91 mmol) was added to a solution of thionyl chloride (10.5 g, 91 mmol) in 100 mL EtOH at 0 ° C. 20.0 mL, 274 mmol) was added dropwise over 30 minutes. The bath was removed and the reaction was allowed to proceed for 16 hours at room temperature. The reaction mixture was concentrated and the brownish residue was titrated with Et ₂ O (2 ×) to give the desired product as a white solid. MS: M + H = 144.

Procedure F1-2 Ethyl (2S)-)-2-{[(4-nitrophenyl) sulfonyl] amino} -4-pentenoate

エチル（２Ｓ）−２−アミノ−４−ペンテン酸塩塩酸塩（１２．０１ｇ、６６．９ｍｍｏｌ）を２２３ｍＬ ＣＨ_２Ｃｌ_２に入れたスラリーに、トリエチルアミン（２０．０ｍＬ、１４０ｍｍｏｌ）および４−塩化ニトロフェニルスルホニル（１４．６７ｇ、６６．２ｍｍｏｌ）を加えた。反応を室温で１６時間進行させた後、ＥｔＯＡｃで希釈し、０．５Ｍ ＨＣｌ（２ｘ）、飽和ＮａＨＣＯ_３水溶液およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、望ましい生成物が得られたが、その後これをそれ以上精製することなく使用した。

To a slurry of ethyl (2S) -2-amino-4-pentenoate hydrochloride (12.01 g, 66.9 mmol) in 223 mL CH ₂ Cl ₂ was added triethylamine (20.0 mL, 140 mmol) and 4-nitrochloride. Phenylsulfonyl (14.67 g, 66.2 mmol) was added. The reaction was allowed to proceed at room temperature for 16 h before being diluted with EtOAc, washed with 0.5 M HCl (2 ×), saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated, The desired product was obtained but was then used without further purification.

Procedure F1-3 Ethyl (2S)-)-2- {isopropyl [(4-nitrophenyl) sulfonyl] amino} -4-pentenoate

エチル（２Ｓ）−）−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−４−ペンテン酸塩（２．４５ｇ、７．４６ｍｍｏｌ）を７５ｍＬ ＴＨＦに入れた溶液に、Ｐｈ_３Ｐ（５．８７ｇ、２２．４ｍｍｏｌ）、ｉ−ＰｒＯＨ（１１．５ｍＬ、１４９ｍｍｏｌ）およびＤＩＡＤ（４．３５ｍＬ、２２．４ｍｍｏｌ）を加えた。室温で１時間攪拌した後、反応混合物を濃縮し、残留物をシリカゲルクロマトグラフィー（２０−＞１００％ＥｔＯＡｃ／ヘキサン）で精製し、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝３７１。

To a solution of ethyl (2S)-)-2-{[(4-nitrophenyl) sulfonyl] amino} -4-pentenoate (2.45 g, 7.46 mmol) in 75 mL THF was added Ph ₃ P (5 .87 g, 22.4 mmol), i-PrOH (11.5 mL, 149 mmol) and DIAD (4.35 mL, 22.4 mmol) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (20-> 100% EtOAc / hexanes) to give the desired product. MS: M + H = 371.

Procedure F1-4 Ethyl (2S, 4E) -2- {isopropyl [(4-nitrophenyl) sulfonyl] amino} -6-oxo-4-heptenoate

エチル（２Ｓ）−）−２−｛イソプロピル［（４−ニトロフェニル）スルホニル］アミノ｝−４−ペンテン酸塩（２．９５ｇ、７．９６ｍｍｏｌ）を８０ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、メチルクロチルケトン（６０％純度、１３．０ｍＬ、８０．０ｍｍｏｌ）およびグラブス第二世代触媒（０．６７６ｇ、０．７９６ｍｍｏｌ）を加えた。反応混合物を６５℃まで１６時間加熱した。残留物をシリカゲルクロマトグラフィー（２０−＞１００％ＥｔＯＡｃ／ヘキサン）で濃縮・精製し、望ましい生成物（１．７０ｇ）が得られた。ＭＳ：Ｍ＋Ｈ＝４１３。

To a solution of ethyl (2S)-)-2- {isopropyl [(4-nitrophenyl) sulfonyl] amino} -4-pentenoate (2.95 g, 7.96 mmol) in 80 mL CH ₂ Cl ₂ was added methyl. Crotyl ketone (60% purity, 13.0 mL, 80.0 mmol) and Grubbs second generation catalyst (0.676 g, 0.796 mmol) were added. The reaction mixture was heated to 65 ° C. for 16 hours. The residue was concentrated and purified by silica gel chromatography (20-> 100% EtOAc / hexane) to give the desired product (1.70 g). MS: M + H = 413.

Procedure F1-5 Ethyl (2S)-)-2- {isopropyl [(4-aminophenyl) sulfonyl] amino} -6-oxoheptanoate

エチル（２Ｓ，４Ｅ）−２−｛イソプロピル［（４−ニトロフェニル）スルホニル］アミノ｝−６−オキソ−４−ヘプテン酸塩（２．２４ｇ、５．４２ｍｍｏｌ）を５４ｍＬ ＥｔＯＨに入れた溶液に、２０％の炭素担持Ｐｄ（ＯＨ）_２（０．７６２ｇ、１．０８ｍｍｏｌ）を加えた。Ｈ_２バルーンを取り付け、フラスコ内の空気を抜き、Ｈ_２（３ｘ）で再充填した。室温で２．５時間攪拌した後、フラスコ内の空気を抜き、Ｎ_２で再充填し、反応混合物をＮ_２下でセライトのパッドを通過させて濾過し、ＣＨ_２Ｃｌ_２で濯いだ。有機物を濃縮して、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝３８５。

To a solution of ethyl (2S, 4E) -2- {isopropyl [(4-nitrophenyl) sulfonyl] amino} -6-oxo-4-heptenoate (2.24 g, 5.42 mmol) in 54 mL EtOH, 20% Pd (OH) _{2 on} carbon (0.762 g, 1.08 mmol) was added. A H ₂ balloon was attached and the flask was evacuated and refilled with H ₂ (3 ×). After stirring at room temperature for 2.5 hours, remove the air in the flask was refilled with N _2, the reaction mixture was filtered through a pad of celite under N _2, rinsed with CH ₂ Cl _2. The organics were concentrated to give the desired product. MS: M + H = 385.

Procedure F1-6 Ethyl (2S, 6S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-{[(S-tert-butylsulfinyl] amino} heptanoate

エチル（２Ｓ）−）−２−｛イソプロピル［（４−アミノフェニル）スルホニル］アミノ｝−６−オキソヘプタン酸塩（２．０７ｇ、５．３８ｍｍｏｌ）を４１ｍＬ ＴＨＦに入れた溶液に、Ｓ−ｔｅｒｔ−ブタンスルフィンアミド（１．９６ｇ、１６．１ｍｍｏｌ）を加えた後、Ｔｉ（ＯＥｔ）_４（５．６０ｍＬ、２６．９ｍｍｏｌ）を加えた。反応混合物を６５℃で１６時間加熱した後、−５０℃に冷却した。水素化ホウ素ナトリウム（１．６３ｇ、４３．０ｍｍｏｌ）を一度に加え、反応混合物を３時間かけて−１０℃まで温めた。次に、−１０℃でＭｅＯＨを加えて反応混合物を急冷した後、ＥＡで希釈した。次に、ブライン（１０ｍＬ）を加え、混合物を室温まで温め、室温で２０分間撹拌した後、セライトのパッドを通過させて濾過し、新鮮なＥＡで濯いだ。次に、濾液を濃縮し、それ以上精製することなく、手順Ｆ１−７で使用した。ＭＳ：Ｍ＋Ｈ＝４９０、ＨＰＬＣによるジアステレオマーの比４−５：１。

To a solution of ethyl (2S)-)-2- {isopropyl [(4-aminophenyl) sulfonyl] amino} -6-oxoheptanoate (2.07 g, 5.38 mmol) in 41 mL THF was added S-tert. -Butanesulfinamide (1.96 g, 16.1 mmol) was added followed by Ti (OEt) ₄ (5.60 mL, 26.9 mmol). The reaction mixture was heated at 65 ° C. for 16 hours and then cooled to −50 ° C. Sodium borohydride (1.63 g, 43.0 mmol) was added in one portion and the reaction mixture was warmed to −10 ° C. over 3 hours. Next, MeOH was added at −10 ° C. to quench the reaction mixture, and then diluted with EA. Brine (10 mL) was then added and the mixture was allowed to warm to room temperature and stirred at room temperature for 20 minutes before being filtered through a pad of celite and rinsed with fresh EA. The filtrate was then concentrated and used in Procedure F1-7 without further purification. MS: M + H = 490, ratio of diastereomers by HPLC 4-5: 1.

Procedure F1-7 Ethyl (2S, 6S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] heptanoic acid hydrochloride

手順Ｆ１−６からの未精製のエチル（２Ｓ，６Ｓ）−２−［［（４−アミノフェニル）スルホニル］（イソプロピル）アミノ］−６−｛［（Ｓ−ｔｅｒｔ−ブチルスルフィニル］アミノ｝ヘプタン酸塩を４１ｍＬ ＭｅＯＨに溶解し、その後、１Ｍ ＨＣｌをＥｔ_２Ｏ（３２．０ｍＬ、３２．０ｍｍｏｌ）に入れたものを加えた。室温で３０分間撹拌した後、反応混合物を濃縮し、結果的に生じるアミンを、それ以上精製することなく後で使用した。ＭＳ：Ｍ＋Ｈ＝３８６。

Crude ethyl (2S, 6S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-{[(S-tert-butylsulfinyl] amino} heptanoic acid from Procedure F1-6 The salt was dissolved in 41 mL MeOH and then 1M HCl in Et ₂ O (32.0 mL, 32.0 mmol) was added.After stirring at room temperature for 30 min, the reaction mixture was concentrated, resulting in The resulting amine was used later without further purification, MS: M + H = 386.

Procedure F1-8 ethyl (2S, 6S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3 -Diphenylpropanoyl} amino) heptanoate

エチル（２Ｓ，６Ｓ）−２−［［（４−アミノフェニル）スルホニル］（イソプロピル）−アミノ］ヘプタン酸塩塩酸塩を、２７ｍＬ ＴＨＦおよび２７ｍＬ 飽和ＮａＨＣＯ_３水溶液に入れた溶液に、メチル［（１Ｓ）−２−［（２，５−ジオキソ−１−ピロリジニル）オキシ］−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩（２．１３ｇ、５．３８ｍｍｏｌ）を加えた。室温で１６時間攪拌した後、反応混合物をＥｔＯＡｃおよびＨ_２Ｏで希釈した。結果的に生じる層を分離し、有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濃縮物をシリカゲルクロマトグラフィー（３０−＞９０％ＥｔＯＡｃ／ヘキサン）で精製し、原位置で形成されたＥｌｌｍａｎスルフィニルイミンの還元により、手順Ｆ１−６で生成した望ましい６−メチルジアステレオマーが手際よく得られた。ＭＳ：Ｍ＋Ｈ＝６６７。

To a solution of ethyl (2S, 6S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) -amino] heptanoic acid hydrochloride in 27 mL THF and 27 mL saturated aqueous NaHCO ₃ solution was added methyl [(1S ) -2-[(2,5-Dioxo-1-pyrrolidinyl) oxy] -1- (diphenylmethyl) -2-oxoethyl] carbamate (2.13 g, 5.38 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc and H ₂ O. The resulting layers were separated and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The concentrate was purified by silica gel chromatography (30-> 90% EtOAc / hexanes) and reduction of the in-situ formed Ellman sulfinylimine neatly produced the desired 6-methyl diastereomer produced in Procedure F1-6. Obtained. MS: M + H = 667.

Procedure F1-9 Methyl [(1S) -2-({(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] 6-hydroxy-1-methylhexyl} amino) -1 -(Diphenylmethyl) -2-oxoethyl] carbamate salt ethyl (2S, 6S) -2-[[(4aminophenyl) sulfonyl] (isopropyl) amino] -6-({(2S) -2-[(methoxy Carbonyl) amino] -3,3-diphenylpropanoyl} amino) heptanoate (2.07 g, 3.10 mmol) in 21 mL THF, LiBH ₄ in THF (2M, 7.76 mL, 15.52 mmol) ) Was added. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0 ° C. and quenched with EtOAc, MeOH and saturated aqueous NH ₄ Cl in that order. The quenched mixture was then diluted with more EtOAc and the resulting organic layer was washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The concentrate was purified by silica gel chromatography (30-> 90% EtOAc / hexanes) to give the desired product as a white blowing agent. MS: M + H = 625. ¹ H NMR (400 MHz, CDCl 3) δ 7.61 (d, J = 8.6 Hz, 2H), 7.32 to 7.18 (m, 5H), 6.67 (d, J = 8.6 Hz, 2H) 5.31 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 8.4 Hz, 1H), 4.75 (t, J = 9.8 Hz, 1H), 4.45 ( d, J = 9.8 Hz, 1H), 4.35 (s, 1H), 3.68 to 3.55 (m, 5H), 3.59 (s, 3H), 3.25 to 3.19 ( m, 1H), 2.81 (s, 1H), 1.38 (d, J = 6.6 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.31 to 1. 23 (m, 3H),). 87 (d, J = 6.5 Hz), 0.84 (m, 3H), 0.615 (s, 1H), 0.38 (s, 1H).

The following examples (Table F) is suitable basic elements _{^{(R 5 COCH = CHMe, ArSO}} 2 Cl, the corresponding active amino acid such as ^{R 1 OH, HO 2 C-} CHR 6 -NHR 7 or hydroxysuccinimide ester) Was made using a procedure similar to that described in the preparation of Example F1. In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal.

Example G1
N-[(1S, 5S) -5- (ethyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide

手順Ｇ１−１ メチル（２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−４−ペンテン酸塩
Ｎ−Ｂｏｃ−Ｌ−アリルグリシン（２ｇ、９．２９ｍｍｏｌ）をアセトンに入れた攪拌溶液に、Ｋ_２ＣＯ_３（２．５７ｇ、１８．５８ｍｍｏｌ）およびメチルヨウ化物（２．６４ｇ、１８．５８ｍｍｏｌ）を加えた。反応混合物を夜通し加熱して還流させ、真空下で濃縮させ、酢酸エチルで溶解し、飽和ＮａＨＣＯ_３で、次にブラインでで洗浄した。有機抽出物をＮａ_２ＳＯ_４で乾燥させ、濾過し、真空下で濃縮させた。すべての分光学的分析は文献と一致し、また粗製材料はそれ以上精製することなく使用した。

Procedure G1-1 Methyl (2S) -2-[(tert-butoxycarbonyl) amino] -4-pentenoate N-Boc-L-allylglycine (2 g, 9.29 mmol) in a stirred solution in acetone, K ₂ CO ₃ (2.57 g, 18.58 mmol) and methyl iodide (2.64 g, 18.58 mmol) were added. The reaction mixture was heated to reflux overnight, concentrated in vacuo, dissolved with ethyl acetate, washed with saturated NaHCO ₃ and then with brine. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. All spectroscopic analyzes were consistent with the literature and the crude material was used without further purification.

Procedure G1-2 Methyl (2S, 4E) -2-[(tert-butoxycarbonyl) amino] -6-oxo-4-heptenoate

メチル（２Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−４−ペンテン酸塩（６．５４ｇ、２８．５ｍｍｏｌ）を６０ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、メチルクロチルケトン（７０％純度、２０．０ｍＬ、１４３．０ｍｍｏｌ）およびグラブス第二世代触媒（１．２１ｇ、１．４３ｍｍｏｌ）を加えた。反応混合物を６５℃まで１６時間加熱した。次に、混合物を濃縮させ、濃縮物をシリカゲルクロマトグラフィー（勾配：４０から８０％ＥＡ／ヘキサン）で精製して、望ましい生成物が得られた。

To a solution of methyl (2S) -2-[(tert-butoxycarbonyl) amino] -4-pentenoate (6.54 g, 28.5 mmol) in 60 mL CH ₂ Cl ₂ was added methyl crotyl ketone (70% Purity, 20.0 mL, 143.0 mmol) and Grubbs second generation catalyst (1.21 g, 1.43 mmol) were added. The reaction mixture was heated to 65 ° C. for 16 hours. The mixture was then concentrated and the concentrate was purified by silica gel chromatography (gradient: 40-80% EA / hexanes) to give the desired product.

Procedure G1-3 Methyl (2S, 4E) -2-[(tert-butoxycarbonyl) amino] -6-oxoheptanoate

メチル（２Ｓ，４Ｅ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−オキソヘプタン酸塩（３．３２ｇ、１２．２４ｍｍｏｌ）を３０ｍＬ ＥｔＯＨに入れた攪拌溶液に、Ｐｄ（ＯＨ）_２（２０％炭素担持、１．７２ｇ、１．２２ｍｍｏｌ）を加えた。Ｈ_２バルーンを取り付け、フラスコ内の空気を抜き、Ｈ_２（３ｘ）で再充填した。３時間後、フラスコの空気を抜き、Ｎ_２で再充填し、反応混合物をＮ_２下でセライトのパッドを通過させて濾過し、ＣＨ_２Ｃｌ_２で濯いだ。有機物を濃縮させて、望ましい生成物が得られた。

To a stirred solution of methyl (2S, 4E) -2-[(tert-butoxycarbonyl) amino] -6-oxoheptanoate (3.32 g, 12.24 mmol) in 30 mL EtOH was added Pd (OH) ₂ ( 20% carbon loading, 1.72 g, 1.22 mmol) was added. A H ₂ balloon was attached and the flask was evacuated and refilled with H ₂ (3 ×). After 3 hours, remove the flask of the air, and refilled with N _2, the reaction mixture was filtered through a pad of celite under N _2, rinsed with CH ₂ Cl _2. The organics were concentrated to give the desired product.

Procedure G1-4 Ethyl- (2S, 6S) -2-[(tert-butoxycarbonyl) amino] -6-{[(S) -tert-butylsulfinyl] amino} heptanoate

メチル（２Ｓ，４Ｅ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−オキソヘプタン酸塩（１．５ｇ、５．４９ｍｍｏｌ）を２０ｍＬ ＴＨＦに入れた攪拌溶液に、Ｓ−ｔｅｒｔ−ブタンスルフィンアミド（１．０ｇ、８．２３ｍｍｏｌ）を加えた後、Ｔｉ（ＯＥｔ）_４（３．４６ｍＬ、１６．５ｍｍｏｌ）を加えた。反応混合物を６５℃で１６時間加熱した後、−５０℃に冷却した。水素化ホウ素ナトリウム（１．０４ｇ、２７．０ｍｍｏｌ）を一度に加え、反応混合物を３時間にわたり−１０℃まで温めた。次に、−１０℃のＭｅＯＨで加えて混合物を急冷した後、ＥＡで希釈し、その後で、ブライン（１０ｍＬ）を加えた。次に、混合物を室温まで温め、室温で２０分間撹拌した後、セライトのパッドを通過させて濾過し、新鮮な酢酸エチルで濯いだ。反応混合物を濃縮し、それ以上精製することなく手順Ｇ１−５で使用した。ＭＳ（Ｍ＋Ｈ＝３９２）、ＨＰＬＣによるジアステレオマーの比４−５：１。

To a stirred solution of methyl (2S, 4E) -2-[(tert-butoxycarbonyl) amino] -6-oxoheptanoate (1.5 g, 5.49 mmol) in 20 mL THF was added S-tert-butanesulfin. Amide (1.0 g, 8.23 mmol) was added followed by Ti (OEt) ₄ (3.46 mL, 16.5 mmol). The reaction mixture was heated at 65 ° C. for 16 hours and then cooled to −50 ° C. Sodium borohydride (1.04 g, 27.0 mmol) was added in one portion and the reaction mixture was warmed to −10 ° C. over 3 hours. The mixture was then quenched with -10 ° C MeOH, diluted with EA, and then brine (10 mL) was added. The mixture was then warmed to room temperature and stirred at room temperature for 20 minutes before being filtered through a pad of celite and rinsed with fresh ethyl acetate. The reaction mixture was concentrated and used in Procedure G1-5 without further purification. MS (M + H = 392), diastereomeric ratio 4-5: 1 by HPLC.

Procedure G1-5 Ethyl- (2S, 6S) -6-amino-2-[(tert-butoxycarbonyl) amino] heptanoate

手順Ｇ１−４からのエチル−（２Ｓ，６Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］アミノ｝ヘプタン酸塩を室温の４１ｍＬ ＭｅＯＨに入れた攪拌溶液に、１Ｍ ＨＣｌをＥｔ_２Ｏに入れたもの（７．６４ｍＬ、７．６４．０ｍｍｏｌ）を加えた。３０分後、反応混合物を飽和ＮａＨＣＯ_３（ｐＨ ７に中和）で急冷し、ＤＣＭで抽出した。有機抽出物を混合し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、真空下で濃縮させた。結果的に生じるアミンをそれ以上精製することなく維持した。ＭＳ（Ｍ＋Ｈ＝２８８）。

Ethyl- (2S, 6S) -2-[(tert-butoxycarbonyl) amino] -6-{[(S) -tert-butylsulfinyl] amino} heptanoate from Procedure G1-4 in 41 mL MeOH at room temperature. To the stirred solution was added 1M HCl in Et ₂ O (7.64 mL, 7.64.0 mmol). After 30 minutes, the reaction mixture was quenched with saturated NaHCO ₃ (neutralized to pH 7) and extracted with DCM. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting amine was maintained without further purification. MS (M + H = 288).

Procedure G1-6 Ethyl (2S, 6S) -2-[(tert-butoxycarbonyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino ) Heptanoate

エチル−（２Ｓ，６Ｓ）−６−アミノ−２−［（ｔｅｒｔ−−ブトキシカルボニル）アミノ］ヘプタン酸塩（０．３００ｇ、１．０４ｍｍｏｌ）を２ｍＬ ＴＨＦおよび２ｍＬ 飽和ＮａＨＣＯ_３水溶液に入れた室温の攪拌溶液に、メチル［（１Ｓ）−２−［（２，５−ジオキソ−１−ピロリジニル）オキシ］−１−（ジフェニルメチル）−２−オキソエチル］カルバミン酸塩（２．１３ｇ、５．３８ｍｍｏｌ）を加えた。１６時間後、反応混合物をＥＡおよびＨ_２Ｏで希釈した。層を分離し、有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた（５５０ｍｇ）。結果として生じる化合物をそれ以上精製することなく使用した。ＭＳ（Ｍ＋Ｈ＝５６９）。

Ethyl- (2S, 6S) -6-amino-2-[(tert-butoxycarbonyl) amino] heptanoate (0.300 g, 1.04 mmol) was placed in 2 mL THF and 2 mL saturated aqueous NaHCO ₃ at room temperature. To the stirred solution was added methyl [(1S) -2-[(2,5-dioxo-1-pyrrolidinyl) oxy] -1- (diphenylmethyl) -2-oxoethyl] carbamate (2.13 g, 5.38 mmol). Was added. After 16 hours, the reaction mixture was diluted with EA and H ₂ O. The layers were separated and the organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated (550 mg). The resulting compound was used without further purification. MS (M + H = 569).

Procedure G1-7 Ethyl (2S, 6S) -2amino-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino) heptanoate

エチル（２Ｓ，６Ｓ）−２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］−６−（｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパノイル）アミノ）ヘプタン酸塩（９０ｍｇ、０．１５８ｍｍｏｌ）を１０ｍＬのＤＣＭに室温で入れた攪拌溶液に、４Ｍ ＨＣｌをジオキサンに入れたもの（１１８μＬ、０．４７４ｍｍｏｌ）を加えた。３０分後、反応混合物を濃縮し、結果的に生じるアミンをそれ以上精製することなく維持した。ＭＳ（Ｍ＋Ｈ＝４７０）。

Ethyl (2S, 6S) -2-[(tert-butoxycarbonyl) amino] -6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino) heptanoate To a stirred solution of (90 mg, 0.158 mmol) in 10 mL DCM at room temperature was added 4M HCl in dioxane (118 μL, 0.474 mmol). After 30 minutes, the reaction mixture was concentrated and the resulting amine was maintained without further purification. MS (M + H = 470).

Procedure G1-8 Methyl 4-{[[1S, 5S-1- (ethoxycarbonyl) -5-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino) hexyl ] (Ethyl) amino] sulfonyl} benzoate

エチル（２Ｓ，６Ｓ）−２アミノ−６−（｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパノイル）アミノ）ヘプタン酸塩（０．１２０ｇ、０．２３７ｍｍｏｌ）を１０ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、トリエチルアミン（１３２μＬ、０．９５０ｍｍｏｌ）および４−エステル塩化スルホニル（５２．９ｍｇ、０．２２５ｍｍｏｌ）を加えた。反応混合物の反応を室温で１６時間進行させた後、ＥＡで希釈し、０．５Ｍ ＨＣｌ（２ｘ）、飽和ＮａＨＣＯ_３水溶液およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、望ましい生成物が得られたが、これをそれ以上精製することなく使用した。

Ethyl (2S, 6S) -2amino-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino) heptanoate (0.120 g, 0.237 mmol) To a solution of 10 mL CH ₂ Cl ₂ was added triethylamine (132 μL, 0.950 mmol) and 4-ester sulfonyl chloride (52.9 mg, 0.225 mmol). The reaction mixture was allowed to proceed at room temperature for 16 hours before being diluted with EA, washed with 0.5 M HCl (2 ×), saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The desired product was obtained which was used without further purification.

Procedure G1-9 (5S, 8S, 12S) -Ethyl-5-benzhydryl-13- (4- (methoxycarbonyl) phenylsulfonyl) -8-methyl-3,6-dioxo-2-oxa-4,17,13 -Triazapentadecane-12-carboxylate

メチル４−｛［［１Ｓ，５Ｓ−１−（エトキシカルボニル）−５−（｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパノイル）アミノ）ヘキシル］（エチル）アミノ］スルホニル｝安息香酸塩（０．０７５ｇ、０．１１２ｍｍｏｌ）を２ｍＬ ＴＨＦに室温で入れた攪拌溶液に、Ｐｈ_３Ｐ（０．０８８ｇ、０．３３７ｍｍｏｌ）、ＥｔＯＨ（２５．９ｍｇ、０．５６２ｍｍｏｌ）およびＤＩＡＤ（６５．５μＬ、０．３３７ｍｍｏｌ）を加えた。１時間後、反応混合物を濃縮し、濃縮物をシリカゲルクロマトグラフィー（２０−＞１００％ＥＡ／ヘキサン）で精製して、望ましい生成物が得られた。ＭＳ（Ｍ＋Ｈ＝６９５）。

Methyl 4-{[[1S, 5S-1- (ethoxycarbonyl) -5-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl) amino) hexyl] (ethyl) To a stirred solution of amino] sulfonyl} benzoate (0.075 g, 0.112 mmol) in 2 mL THF at room temperature, Ph ₃ P (0.088 g, 0.337 mmol), EtOH (25.9 mg, 0.562 mmol). ) And DIAD (65.5 μL, 0.337 mmol) were added. After 1 hour, the reaction mixture was concentrated and the concentrate was purified by silica gel chromatography (20-> 100% EA / hexane) to give the desired product. MS (M + H = 695).

Procedure G1-10 N-[(1S, 5S) -5- (ethyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamido ethyl (5S, 8S, 12S) -ethyl-5-benzhydryl-13- (4- (methoxycarbonyl) phenylsulfonyl) -8-methyl-3,6-dioxo-2-oxa-4 , 17,13-Triazapentadecane-12-carboxylate (0.050 g, 0.072 mmol) in 1.5 mL THF at room temperature and LiBH ₄ in THF (2M, 719 μL, 0.719 mmol) was added. After 16 hours, the reaction mixture was cooled to 0 ° C. and quenched by adding EA, MeOH and saturated aqueous NH ₄ Cl in that order. The mixture was then diluted with more EA and the organics were washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The concentrate was purified by silica gel chromatography (30-> 90% EA / hexane) to give the desired product as a white solid. MS (M + H = 626). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.32 to 7.18 (m, 10H ), 6.23 (d, J = 7.2 Hz, 1H), 5.30 (d, J = 9.2 Hz, 1H), 4.91 to 4.74 (m, 3H), 3.57 (s) 3H), 3.53 to 3.49 (m, 5H), 3.35 (m, 2H), 3.13 to 3.07 (m, 1H), 2.89 to 2.60 (br s, 5H), 1.31 to 1.23 (m, 3H), 0.89 (m, 2H), 0.70 (d, J = 6.8 Hz, 2H).

The following examples (Table G) the appropriate basic elements _{^{(R 5 COCH = CHMe, ArSO}} 2 Cl, the corresponding active amino acid such as ^{R 1 OH, HO 2 C-} CHR 6 -NHR 7 or hydroxysuccinimide ester) Was made using a procedure similar to that described in the preparation of Example G1. In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal. See also the footnote in Table G that describes a modification of the procedure for preparing the compound of Example G15.

Example H1
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide

手順Ｈ１−１ メチル（２Ｓ、４Ｅ）−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−６−オキソ−４−ヘキセン酸塩

Procedure H1-1 Methyl (2S, 4E) -2-{[(4-nitrophenyl) sulfonyl] amino} -6-oxo-4-hexenoate

メチル（２Ｓ）−）−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−４−ペンテン酸塩（５．００ｇ、１５．９１ｍｍｏｌ）（手順Ｆ１−１および手順Ｆ１−２で説明したとおりに、第一の手順でＥｔＯＨをＭｅＯＨに置き換えて合成）を２００ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、クロトンアルデヒド（５．２７ｍＬ、６３．６ｍｍｏｌ）およびグラブス第二世代触媒（１．３５ｇ、１．５９ｍｍｏｌ）を加えた。反応混合物を６０℃で３０分加熱し、濃縮して、シリカゲルクロマトグラフィー（１０−＞７０％ＥｔＯＡｃ／ヘキサン）で精製し、表題の化合物が得られた。

Methyl (2S)-)-2-{[(4-nitrophenyl) sulfonyl] amino} -4-pentenoate (5.00 g, 15.91 mmol) (as described in Procedure F1-1 and Procedure F1-2) In a first procedure, EtOH was replaced with MeOH in 200 mL CH ₂ Cl ₂ in a solution of crotonaldehyde (5.27 mL, 63.6 mmol) and Grubbs second generation catalyst (1.35 g, 1 .59 mmol) was added. The reaction mixture was heated at 60 ° C. for 30 min, concentrated and purified by silica gel chromatography (10-> 70% EtOAc / hexanes) to give the title compound.

Procedure H1-2 Methyl (2S, 4E, 6E) -6-{[(S-tert-butylsulfinyl) imino} -2-{[(4-nitrophenyl) sulfonyl] amino} -4-hexenoate

メチル（２Ｓ、４Ｅ）−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−６−オキソ−４−ヘキセン酸塩を５８ｍＬ ＴＨＦに０℃で入れた溶液に、Ｓ−ｔｅｒｔ−ブタンスルフィンアミドを加えた後、Ｔｉ（ＯＥｔ）_４を加えた。反応混合物を数時間かけて徐々に室温まで温めた。１８時間後、反応混合物を０℃に冷やし、ＥｔＯＡｃで希釈した。次に、ブライン（１０ｍＬまで）を加え、混合物を室温で２０分間激しく撹拌した。次に反応混合物をセライトのパッドを通過させて濾過し、新鮮なＥｔＯＡｃで濯いだ。次に、濾過物を濃縮させ、濃縮物をシリカゲルクロマトグラフィー（３０−＞８０％ＥｔＯＡｃ／ヘキサン）で精製して、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝４６０。

To a solution of methyl (2S, 4E) -2-{[(4-nitrophenyl) sulfonyl] amino} -6-oxo-4-hexenoate in 58 mL THF at 0 ° C. was added S-tert-butanesulfinamide. And then Ti (OEt) ₄ was added. The reaction mixture was gradually warmed to room temperature over several hours. After 18 hours, the reaction mixture was cooled to 0 ° C. and diluted with EtOAc. Then brine (up to 10 mL) was added and the mixture was stirred vigorously at room temperature for 20 minutes. The reaction mixture was then filtered through a pad of celite and rinsed with fresh EtOAc. The filtrate was then concentrated and the concentrate was purified by silica gel chromatography (30-> 80% EtOAc / hexanes) to give the desired product. MS: M + H = 460.

Procedure H1-3 Methyl (2S, 4E, 6R) -6-{[(tert-butylsulfinyl] amino} -7,7,7-trifluoro-2-{[(4-nitrophenyl) sulfonyl] amino}- 4-heptenoate

メチル（２Ｓ、４Ｅ、６Ｅ）−６−｛［（Ｓ−ｔｅｒｔ−ブチルスルフィニル］イミノ｝−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−４−ヘキセン酸塩（１．６２ｇ、３．５９ｍｍｏｌ）を３６ｍＬ ＴＨＦに０℃で入れた溶液に、ＴＭＳ−ＣＦ_３（１．２８ｇ、８．９８ｍｍｏｌ）を加え後、ＴＭＡＦ（０．８７ｍＬ、８．９８ｍｍｏｌ）を加えた。０℃で１．５時間撹拌した後、反応混合物を飽和ＮＨ_４Ｃｌ水溶液を加えて急冷し、ＥｔＯＡｃおよびＨ_２Ｏで希釈した。次に層を分離し、有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、表題の生成物が得られたが、その後これを手順Ｈ１−４でそれ以上精製することなく使用した。ＭＳ：Ｍ＋Ｈ＝５１６。

Methyl (2S, 4E, 6E) -6-{[(S-tert-butylsulfinyl] imino} -2-{[(4-nitrophenyl) sulfonyl] amino} -4-hexenoate (1.62 g, 3 .59 mmol) in 36 mL THF at 0 ° C., TMS-CF ₃ (1.28 g, 8.98 mmol) was added followed by TMAF (0.87 mL, 8.98 mmol). After stirring for 5 h, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc and H ₂ O. The layers were then separated and the organics were washed with brine and washed over Na ₂ SO ₄ . Drying, filtration and concentration gave the title product which was then used without further purification in procedures H1-4, MS: M + H = 516.

Procedure H1-4 Methyl (2S, 4E, 6R) -6-amino-7,7,7-trifluoro-2-{[(4-nitrophenyl) sulfonyl] amino} -4-heptenoate hydrochloride

手順Ｈ１−３からの未精製のメチル（２Ｓ、４Ｅ、６Ｒ）−６−｛［（ｔｅｒｔ−ブチルスルフィニル］アミノ｝−７，７，７−トリフルオロ−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−４−ヘプテン酸塩（１．８０ｇ、３．４９ｍｍｏｌ）を２９ｍＬ ＭｅＯＨに入れた溶液に、４Ｍ ＨＣｌをジオキサンに入れたもの（７．０ｍＬ、２７．９ｍｍｏｌ）を加えた。室温で２時間攪拌した後、反応混合物を濃縮し、それ以上精製することなく手順Ｈ１−５で使用した。ＭＳ：Ｍ＋Ｈ＝４１２。

Crude methyl (2S, 4E, 6R) -6-{[(tert-butylsulfinyl] amino} -7,7,7-trifluoro-2-{[(4-nitrophenyl) from procedure H1-3 To a solution of sulfonyl] amino} -4-heptenoate (1.80 g, 3.49 mmol) in 29 mL MeOH was added 4M HCl in dioxane (7.0 mL, 27.9 mmol). After stirring at rt for 2 h, the reaction mixture was concentrated and used in procedures H1-5 without further purification, MS: M + H = 412.

Procedure H1-5 Methyl (2S, 4E, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} Amino) -2-{[(4-nitrophenyl) sulfonyl] amino} heptenoate

手順Ｈ１−４からの未精製のメチル（２Ｓ、４Ｅ、６Ｒ）−６−アミノ−７，７，７−トリフルオロ−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝−４−ヘプテン酸塩塩酸塩（１．４０ｇ、３．４０ｍｍｏｌ）および２Ｓ−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパン酸（１．１２ｇ、３．７４ｍｍｏｌ）を３８ｍＬ ＤＭＦに入れた溶液に、ジイソプロピルエチルアミン（１．５０ｍＬ、８．５１ｍｍｏｌ）およびＰｙＢｒＯＰ（２．０６ｇ、４．４２ｍｍｏｌ）を加えた。反応混合物の反応を室温で１６時間撹拌して進行させた後、飽和ＮａＨＣＯ_３水溶液を加えて急冷した。次に、急冷した反応混合物をＥｔＯＡｃで希釈し、結果的に生じる層を分離して、有機物を３Ｍ ＬｉＣｌ（３ｘ）およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濃縮物をシリカゲルクロマトグラフィー（２０−＞８０％ＥｔＯＡｃ／ヘキサン）で精製して、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝６９３。

Crude methyl (2S, 4E, 6R) -6-amino-7,7,7-trifluoro-2-{[(4-nitrophenyl) sulfonyl] amino} -4-heptenoic acid from procedure H1-4 To a solution of hydrochloride hydrochloride (1.40 g, 3.40 mmol) and 2S-2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoic acid (1.12 g, 3.74 mmol) in 38 mL DMF, Diisopropylethylamine (1.50 mL, 8.51 mmol) and PyBrOP (2.06 g, 4.42 mmol) were added. The reaction mixture was allowed to proceed with stirring at room temperature for 16 hours, and then quenched by adding saturated aqueous NaHCO ₃ solution. The quenched reaction mixture is then diluted with EtOAc and the resulting layers are separated and the organics are washed with 3M LiCl (3x) and brine, dried over Na ₂ SO ₄ , filtered and concentrated. It was. The concentrate was purified by silica gel chromatography (20-> 80% EtOAc / hexanes) to give the desired product. MS: M + H = 693.

Procedure H1-6 Methyl (2S, 4E, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} Amino) -2-[[(4-nitrophenyl) sulfonyl] (propyl) amino] heptenoate

メチル（２Ｓ、４Ｅ、６Ｒ）−）−７，７，７−トリフルオロ−６−（｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパノイル｝アミノ）−２−｛［（４−ニトロフェニル）スルホニル］アミノ｝ヘプテン酸塩（０．２４０ｇ、０．３４０ｍｍｏｌ）を４ｍＬ ＴＨＦに入れた溶液に、ｎ−プロパノール（０．１３０ｍＬ、１．７０ｍｍｏｌ）、Ｐｈ３Ｐ（２６７ｍｇ、１．０２ｍｍｏｌ）およびＤＩＡＤ（０．２００ｍＬ、１．０２ｍｍｏｌ）を加えた。１６時間後、反応物を濃縮させ、シリカゲルクロマトグラフィー（２０−＞５５％ＥｔＯＡｃ／ヘキサン）により精製して、望ましい生成物（０．２５０ｇ）が白色の発泡剤として得られた。ＭＳ：Ｍ＋Ｈ＝７３５。

Methyl (2S, 4E, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino) -2 -To a solution of {[(4-nitrophenyl) sulfonyl] amino} heptenoate (0.240 g, 0.340 mmol) in 4 mL THF, n-propanol (0.130 mL, 1.70 mmol), Ph3P (267 mg). 1.02 mmol) and DIAD (0.200 mL, 1.02 mmol) were added. After 16 hours, the reaction was concentrated and purified by silica gel chromatography (20-> 55% EtOAc / hexanes) to give the desired product (0.250 g) as a white blowing agent. MS: M + H = 735.

Procedure H1-7 Methyl (2S, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino) -2-[[(4-Aminophenyl) sulfonyl] (propyl) amino] heptanoate

メチル（２Ｓ、４Ｅ、６Ｒ）−）−７，７，７−トリフルオロ−６−（｛（２Ｓ）−２−［（メトキシカルボニル）アミノ］−３，３−ジフェニルプロパノイル｝アミノ）−２−［［（４−ニトロフェニル）スルホニル］（プロピル）アミノ］ヘプテン酸塩（０．２５０ｇ、０．３４０ｍｍｏｌ）を３ｍＬ ＥｔＯＨに入れた溶液に、Ｐｄ（ＯＨ）２（２０％炭素担持、７１．７ｍｇ、０．１０２ｍｍｏｌ）を加えた。Ｈ_２バルーンを取り付け、フラスコ内の空気を抜き、Ｈ_２（３ｘ）で再充填した。室温で３時間攪拌した後、フラスコ内の空気を抜き、Ｎ_２で再充填し、および反応混合物をＮ_２下でセライトのパッドを通過させて濾過し、ＣＨ_２Ｃｌ_２で濯いだ。有機物を濃縮して、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝７０７。

Methyl (2S, 4E, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl) amino] -3,3-diphenylpropanoyl} amino) -2 -[[(4-Nitrophenyl) sulfonyl] (propyl) amino] heptenoate (0.250 g, 0.340 mmol) in 3 mL EtOH was added to a solution of Pd (OH) 2 (20% on carbon, 71. 7 mg, 0.102 mmol) was added. A H ₂ balloon was attached and the flask was evacuated and refilled with H ₂ (3 ×). After stirring for 3 hours at room temperature, remove the air inside the flask was refilled with N _2, and the reaction mixture was filtered through a pad of celite under N _2, rinsed with CH ₂ Cl _2. The organics were concentrated to give the desired product. MS: M + H = 707.

Procedure H1-8 Methyl [(1S) -2-{[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl ] Amino} -1- (diphenylmethyl) -2-oxoethyl] carbamate methyl (2S, 6R)-)-7,7,7-trifluoro-6-({(2S) -2-[(methoxycarbonyl ) Amino] -3,3-diphenylpropanoyl} amino) -2-[[(4-aminophenyl) sulfonyl] (propyl) amino] heptanoate (0.240 g, 0.340 mmol) in 3.5 mL THF. To the charged solution was added 2M LiBH ₄ (0.680 mL, 1.36 mmol). After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0 ° C. and quenched by the sequential addition of EtOAc, MeOH and saturated aqueous NH 4 Cl. The quenched mixture was then diluted with more EtOAc and the organics were washed with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The concentrate was purified by preparative HPLC (5-> 95% CH3CN / H2O). MS: M + H = 679. ¹ H NMR (400 MHz, MeOD) δ 8.48 (d, J = 9.4 Hz, 1H), 7.54 (d, J = 9.8 Hz, 2H), 7.37 to 7.26 (m, 4H) , 7.24 to 7.14 (m, 6H), 6.76 (d, J = 9.8 Hz, 2H), 5.08 (d, J = 11.7 Hz, 1H), 4.34 (d, J = 11.7 Hz, 1H), 4.12 to 4.11 (m, 1H), 3.52 (s, 3H), 3.49 to 3.31 (m, 4H), 3.09 to 2. 96 (m, 2H), 1.63 to 1.43 (m, 3H), 1.33 to 1.27 (m, 1H), 1.18 to 1.09 (m, 2H), 0.97 ( t, J = 7.5 Hz, 3H), 0.58 (m, 2H).

The following examples (Table H) show the preparation of Example H1 using the appropriate building blocks (the corresponding active amino acids such as R ¹ OH, HO ₂ C—CHR ⁶ —NHR ⁷ or hydroxysuccinate). It was created using a procedure similar to that described in. In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal.

Example I1
2-Chloro-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl}-(isobutyl) amino] hexyl} -Nα- (methoxy Carbonyl) -L-phenylalaninamide

手順Ｉ−１ エチル（２Ｓ）−６−オキソ−２−ピペリジンカルボン酸塩
６−オキソ−Ｌ−ピコリン酸（５．００ｇ、３４．９ｍｍｏｌ）を１２０ｍＬ ＥｔＯＨに入れた溶液に、１ｍＬアリコットに入れた塩化チオニル（２５．５ｍＬ、３４９ｍｍｏｌ）を３０分間にわたり加えた。室温で１６時間攪拌した後、反応混合物を濃縮させて、未特定の不純物を含む望ましい生成物が黄色い油として得られた。ＭＳ：Ｍ＋Ｈ＝１７２。生成物をそれ以上精製することなく手順Ｉ−２で使用した。

Procedure I-1 Ethyl (2S) -6-oxo-2-piperidinecarboxylate 6-Oxo-L-picolinic acid (5.00 g, 34.9 mmol) was added to a solution of 120 mL EtOH in a 1 mL aliquot. Thionyl chloride (25.5 mL, 349 mmol) was added over 30 minutes. After stirring at room temperature for 16 hours, the reaction mixture was concentrated to give the desired product containing unspecified impurities as a yellow oil. MS: M + H = 172. The product was used in procedure I-2 without further purification.

Procedure I-2 1-tert-butyl 2-ethyl- (2S) -6-oxo-2-piperidinecarboxylate ethyl (2S) -6-oxo-2-piperidinecarboxylate (3.79 g, 22.1 mmol ) In 15.8 mL CH ₃ CN was added Boc ₂ O (9.66 g, 44.3 mmol) and DMAP (5.41 g, 44.3 mmol). After stirring at room temperature for 6 hours, the reaction mixture was concentrated and purified by silica gel chromatography (0-> 70% EtOAc / hexanes) to give the desired product. MS: M + H = 272.

Procedure I-3 Ethyl (2S) -2-[(tert-butoxycarbonyl) amino] -6-cyclopropyl-6-oxohexanoate

１−ｔｅｒｔ−ブチル２−エチル−（２Ｓ）−６−オキソ−２−ピペリジンカルボン酸塩（０．４６０ｇ、１．６９ｍｍｏｌ）を２．８３ｍＬ ＴＨＦに−７８℃で入れた溶液に、臭化シクロプロピルマグナシウムをＴＨＦに入れたもの（０．５Ｍ、４．０７ｍＬ、２．０３ｍｍｏｌ）を加えた。反応混合物を−３０℃まで３時間かけて温めた後、飽和ＮＨ_４Ｃｌ水溶液およびＥｔＯＡｃを加えて急冷した。層を分離し、および有機物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させた。濾過物をシリカゲルクロマトグラフィー（４０−＞１００％ＥｔＯＡｃ／ヘキサン）により精製し、望ましい生成物が得られた。ＭＳ：Ｍ＋Ｈ＝３１４。

To a solution of 1-tert-butyl 2-ethyl- (2S) -6-oxo-2-piperidinecarboxylate (0.460 g, 1.69 mmol) in 2.83 mL THF at −78 ° C. was added cyclobromide. A solution of propylmagnesium in THF (0.5 M, 4.07 mL, 2.03 mmol) was added. The reaction mixture was warmed to −30 ° C. over 3 hours and then quenched with saturated aqueous NH ₄ Cl and EtOAc. The layers were separated and the organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The filtrate was purified by silica gel chromatography (40-> 100% EtOAc / hexanes) to give the desired product. MS: M + H = 314.

The ketone obtained from Procedure I-3 can be converted to (R) -tert-butanesulfinylimine production (as in Procedure F1-6), diastereoselective imine reduction (as in Procedure F1-7), auxiliary deprotection ( Conjugation with (2S) -3- (2-chlorophenyl) -2-[(methoxycarbonyl) amino] propanoic acid (as in Procedure B1-11, EDC and HOAt Used instead), Boc removal (as in procedure B1-10), sulfonylation with 4-carbomethoxysulfonyl chloride (as in procedure F1-2), Mitsunobu reaction (as in procedure F1-3, isobutanol is converted to isoprona It was as instead used) and diesters reduction (Step F1-9 of Nord, 7 eq of LiBH _4), final compound 2-chloro -N- { 1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide did. MS: M + H = 638, 639 (Cl pattern). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 7.8 Hz, 2H), 7.49 to 7.44 (m, 3H), 7.28 to 7.16 (m, 3H), 7.23 (s, 1H), 5.34 (d, J = 8.2 Hz, 1H), 4.80 (dd, J = 8.7, 4.0 Hz, 1H), 4.69 (d, J = 12.6 Hz, 1H), 4.40 (d, J = 7.4 Hz, 1H), 4.28 (s, 1H), 3.65 (s, 3H), 3.61 to 3.49 (m) 2H), 3.38 (s, 1H), 3.16 to 3.10 (m, 3H), 2.77 to 2.73 (m, 2H), 2.60 (m, 1H), 1. From 884 (m, 1H), 1.16 (m, 2H), 0.99 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.99 0.91 m, 2H), 0.39 from 0.30 (m, 4H), 0.14 (m, 1H), 0.03 (m, 2H).

The following examples (Table I) use the appropriate building blocks (corresponding active amino acids such as R ⁵ MgX, ArSO ₂ Cl, R ¹ OH, HO ₂ C—CHR ⁶ —NHR ⁷ or hydroxysuccinate) And was prepared using a procedure similar to that described in the preparation of Example I1. In some cases, NHR ⁷ was initially protected as Boc, but the last procedure required acidic Boc removal.

Example J1
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide

手順Ｊ１−１：メチル６−（ベンジルオキシ）−Ｌ−ノルロイシナート塩酸塩

Procedure J1-1: Methyl 6- (benzyloxy) -L-norleucinate hydrochloride

メチル６−（ベンジルオキシ）−Ｌ−ノルロイシン（ＡｄｖａｎｃｅｄＣｈｅｍＴｅｃｈ ＹＬ２３７５、１０．９２ｇ、４６ｍｍｏｌ）をＭｅＯＨ（４６０ｍＬ）に入れた懸濁液を通して、ＨＣｌ（ｇ）を１０分間泡立てた。次に、反応混合物を５０℃で４時間加熱した後、室温まで冷ました。次に、窒素ガスをその混合物を通して１０分間泡立て、その後、混合物を真空内で濃縮させ、ＤＣＭから３回再濃縮して、望ましい生成物が白色の固体として得られた。ＭＳ Ｍ＋１＝２５２。

HCl (g) was bubbled through a suspension of methyl 6- (benzyloxy) -L-norleucine (AdvancedChemTech YL2375, 10.92 g, 46 mmol) in MeOH (460 mL) for 10 minutes. The reaction mixture was then heated at 50 ° C. for 4 hours and then cooled to room temperature. Nitrogen gas was then bubbled through the mixture for 10 minutes, after which the mixture was concentrated in vacuo and reconcentrated from DCM three times to give the desired product as a white solid. MS M + 1 = 252.

Procedure J1-2: Methyl 6- (benzyloxy) -N-{[4- (methoxycarbonyl) phenyl] sulfonyl} -L-norleucineate

メチル６−（ベンジルオキシ）−Ｌ−ノルロイシナート塩酸塩（１５ｇ、５２．１ｍｍｏｌ）をＤＣＭ（２６１ｍＬ）に入れた溶液に、トリエチルアミン（１５．９８ｍＬ、１１５ｍｍｏｌ）を加えた後、４−カルボメトキシ−塩化フェニルスルホニル（１２．４８ｇ、５３．２ｍｍｏｌ）を何回かに分けて加えた。室温で１５分間撹拌した後、反応混合物を真空内で３分の１の容積まで濃縮し、ＥｔＯＡｃで希釈し、１０％ＫＨＳＯ_４、飽和ＮａＨＣＯ_３水溶液、ブラインの順で洗浄した後、硫酸ナトリウム上で乾燥させ、真空内で濃縮して、望ましい生成物が粗製の固体として得られた。ＭＳ Ｍ＋１＝４５０。

To a solution of methyl 6- (benzyloxy) -L-norleucineate hydrochloride (15 g, 52.1 mmol) in DCM (261 mL) was added triethylamine (15.98 mL, 115 mmol), followed by 4-carbomethoxy-chloride. Phenylsulfonyl (12.48 g, 53.2 mmol) was added in several portions. After stirring at room temperature for 15 minutes, the reaction mixture was concentrated in vacuo to a third volume, diluted with EtOAc, washed with 10% KHSO ₄ , saturated aqueous NaHCO ₃ , brine, and then over sodium sulfate. And concentrated in vacuo to give the desired product as a crude solid. MS M + 1 = 450.

Procedure J1-3: methyl 6- (benzyloxy) -N-{[4- (methoxycarbonyl) phenyl] sulfonyl} -N- (3-methylbutyl) -L-norleucinate

メチル６−（ベンジルオキシ）−Ｎ−｛［４−（メトキシカルボニル）フェニル］−スルホニル｝−Ｌ−ノルロイシナート（３ｇ、６．６７ｍｍｏｌ）、トリフェニルホスフィン（２．６３ｇ、１０．０１ｍｍｏｌ）および３−メチル−１−ブタノール（３．６４ｍＬ、３３．４ｍｍｏｌ）をＴＨＦ（６６．７ｍＬ）に入れた溶液に、ＤＥＡＤ（１．５８５ｍＬ、１０．０１ｍｍｏｌ）を滴下して加えた。反応混合物を室温で夜通し撹拌し、真空内で濃縮し、フラッシュクロマトグラフィー（３００ｇシリカ、１０から４０％ＥｔＯＡｃ／ヘキサン）で精製して、望ましい生成物が透明な油として得られた。ＭＳ Ｍ＋Ｎａ＝５４２。

Methyl 6- (benzyloxy) -N-{[4- (methoxycarbonyl) phenyl] -sulfonyl} -L-norleucineate (3 g, 6.67 mmol), triphenylphosphine (2.63 g, 10.1 mmol) and 3- To a solution of methyl-1-butanol (3.64 mL, 33.4 mmol) in THF (66.7 mL), DEAD (1.585 mL, 10.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo and purified by flash chromatography (300 g silica, 10 to 40% EtOAc / hexanes) to give the desired product as a clear oil. MS M + Na = 542.

Procedure J1-4: N-[(1S) -5- (benzyloxy) -1- (hydroxymethyl) pentyl] -4- (hydroxymethyl) -N- (3-methylbutyl) benzenesulfonamide

メチル６−（ベンジルオキシ）−Ｎ−｛［４−（メトキシカルボニル）フェニル］−スルホニル｝−Ｎ−（３−メチルブチル）−Ｌ−ノルロイシナート（３ｇ、５．７７ｍｍｏｌ）をＴＨＦ（３８．５ｍＬ）に入れ、０℃に冷却した溶液に、ＬＡＨ（Ｅｔ_２Ｏ中１Ｍ、１１．５５ｍＬ、１１．５５ｍｍｏｌ）を加え、反応混合物を０℃で２０分間撹拌した。次に、水（４５６μＬ）を滴下して加えた後、４５６μＬの１５％ＮａＯＨ、１３６８μＬの水の順で滴下して加えた。室温で５分間激しく撹拌した後、反応混合物をセライト上で濾過し、真空内で濃縮して、望ましい生成物が得られた。ＭＳ Ｍ＋１＝４６４。

Methyl 6- (benzyloxy) -N-{[4- (methoxycarbonyl) phenyl] -sulfonyl} -N- (3-methylbutyl) -L-norleucineate (3 g, 5.77 mmol) in THF (38.5 mL). To the solution cooled to 0 ° C., LAH (1M in Et ₂ O, 11.55 mL, 11.55 mmol) was added and the reaction mixture was stirred at 0 ° C. for 20 min. Next, water (456 μL) was added dropwise, followed by dropwise addition in the order of 456 μL of 15% NaOH and 1368 μL of water. After stirring vigorously at room temperature for 5 minutes, the reaction mixture was filtered over celite and concentrated in vacuo to give the desired product. MS M + 1 = 464.

Procedure J1-5: N-[(1S) -5- (benzyloxy) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) pentyl] -4-({[tert-butyl (diphenyl) Silyl] oxy} methyl) -N- (3-methylbutyl) benzenesulfonamide

Ｎ−［（１Ｓ）−５−（ベンジルオキシ）−１−（ヒドロキシメチル）ペンチル］−４−（ヒドロキシメチル）−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（２．６８ｇ、５．７８ｍｍｏｌ）、イミダゾール（８６６ｍｇ、１２．７２ｍｍｏｌ）およびＤＭＡＰ（７１ｍｇ、０．５７８ｍｍｏｌ）をＤＣＭ（５８ｍＬ）に入れた溶液に、ＴＢＤＰＳＣｌ（３．０４ｍＬ、１１．８５ｍｍｏｌ）を加えた。反応混合物を室温で夜通し撹拌し、真空内で３分の１の容積まで濃縮し、Ｅｔ_２Ｏで希釈し、１０％ＫＨＳＯ_４、飽和ＮａＨＣＯ_３水溶液、およびブラインで洗浄した後、硫酸ナトリウム上で乾燥させ、真空内で濃縮し、フラッシュクロマトグラフィー（３００ｇシリカ、０から３０％ＥｔＯＡｃ／ヘキサン）で精製して、望ましい生成物が得られた。

N-[(1S) -5- (benzyloxy) -1- (hydroxymethyl) pentyl] -4- (hydroxymethyl) -N- (3-methylbutyl) benzenesulfonamide (2.68 g, 5.78 mmol), To a solution of imidazole (866 mg, 12.72 mmol) and DMAP (71 mg, 0.578 mmol) in DCM (58 mL) was added TBDPSCl (3.04 mL, 11.85 mmol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo to a third volume, diluted with Et ₂ O, washed with 10% KHSO ₄ , saturated aqueous NaHCO ₃ , and brine, then over sodium sulfate. Dried, concentrated in vacuo and purified by flash chromatography (300 g silica, 0-30% EtOAc / hexanes) to give the desired product.

Procedure J1-6: 4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-[(1S) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5 Hydroxypentyl] -N- (3-methylbutyl) benzenesulfonamide

Ｎ−［（１Ｓ）−５−（ベンジルオキシ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−ペンチル］−４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（５．４４ｇ、５．７８ｍｍｏｌ）をＥｔＯＨ（１１６ｍＬ）に入れた溶液を、アルゴンで真空パージし、１０％Ｐｄ／Ｃ（３．０８ｇ）をアルゴン流下で非常に慎重に加えた。反応混合物を１気圧Ｈ_２、室温で１６時間水素化した。反応混合物をアルゴンで真空パージし、１０％Ｐｄ／Ｃ（５ｇ）をアルゴン流下で非常に慎重に加え、反応混合物を再び１気圧Ｈ_２、室温で４日間実行した。次に、反応混合物をＮ_２流下で慎重に濾過し、ＥｔＯＨで濯ぎ、真空内で濃縮して、望ましい生成物が得られた。

N-[(1S) -5- (benzyloxy) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -pentyl] -4-({[tert-butyl (diphenyl) silyl] oxy} A solution of methyl) -N- (3-methylbutyl) benzenesulfonamide (5.44 g, 5.78 mmol) in EtOH (116 mL) was vacuum purged with argon and 10% Pd / C (3.08 g) was added. Added very carefully under a stream of argon. The reaction mixture was hydrogenated at 1 atm H ₂ at room temperature for 16 hours. The reaction mixture was vacuum purged with argon, 10% Pd / C (5 g) was added very carefully under a stream of argon, and the reaction mixture was again run at 1 atm H ₂ at room temperature for 4 days. The reaction mixture was carefully filtered under a stream of N _2, rinsed with EtOH, and concentrated in vacuo, the desired product was obtained.

Procedure J1-7: 4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-[(1S) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5 Oxopentyl] -N- (3-methylbutyl) benzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−５−ヒドロキシペンチル］−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（４ｇ、４．７ｍｍｏｌ）およびＮＭＯ（６６１ｍｇ、５．６５ｍｍｏｌ）をＤＣＭ（４７ｍＬ）に入れた溶液に、３ｇの４Ａふるいを加え、活性化して、反応混合物を室温で５分間撹拌した。次に、ＴＰＡＰ（１６５ｍｇ、０．４７ｍｍｏｌ）を何回かに分けて加え、反応混合物を室温で４５分間撹拌し、シリカゲルのプラグ上で濾過し、２５％ＥｔＯＡｃ／ヘキサンで溶出し、濃縮の後望ましい生成物が得られた。

4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-[(1S) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5-hydroxypentyl] -N To a solution of-(3-methylbutyl) benzenesulfonamide (4 g, 4.7 mmol) and NMO (661 mg, 5.65 mmol) in DCM (47 mL) was added 3 g 4A sieve to activate and the reaction mixture was Stir at room temperature for 5 minutes. TPAP (165 mg, 0.47 mmol) was then added in several portions and the reaction mixture was stirred at room temperature for 45 minutes, filtered over a plug of silica gel, eluted with 25% EtOAc / hexanes, and after concentration. The desired product was obtained.

Procedure J1-8: (6S, 10E) -6-[{[4-({[tert-butyl (diphenyl) silyl] oxy} methyl) phenyl] sulfonyl} (3-methylbutyl) amino] -2,2,13 , 13-Tetramethyl-3,3-diphenyl-4-oxa-12-thionia-11-aza-3-silatetradec-10-ene-12-olate

４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−５−オキソペンチル］−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（２．０ｇ、２．７ｍｍｏｌ）を窒素雰囲気下で塩化メチレン（２５ｍＬ）に溶解した。硫酸マグネシウム（２．８ｇ、２３．６ｍｍｏｌ）、（Ｒ）−（＋）−ｔｅｒｔ−ブタンスルフィンアミド（４３０ｍｇ、３．５ｍｍｏｌ）、ピリジニウムｐ−トルエン−スルホナート（３０ｍｇ、０．１１ｍｍｏｌ）を、攪拌溶液に固体としてすべて何回かに分けて加えた。反応を室温で３６時間撹拌した後、セライトパッド上で濾過し、真空内で濃縮した。結果的に生じる粗製の油を、シリカゲルクロマトグラフィー（３００ｇ、０から４０％酢酸エチル／ヘキサンの勾配）を使用して精製し、望ましい生成物が得られた。

4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-[(1S) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5-oxopentyl] -N -(3-Methylbutyl) benzenesulfonamide (2.0 g, 2.7 mmol) was dissolved in methylene chloride (25 mL) under a nitrogen atmosphere. Magnesium sulfate (2.8 g, 23.6 mmol), (R)-(+)-tert-butanesulfinamide (430 mg, 3.5 mmol), pyridinium p-toluene-sulfonate (30 mg, 0.11 mmol) in a stirred solution Added as a solid all in portions. The reaction was stirred at room temperature for 36 hours, then filtered over a celite pad and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (300 g, gradient from 0 to 40% ethyl acetate / hexanes) to give the desired product.

Procedure J1-9: (6S, 10S) -6-[{[4-({[tert-butyl (diphenyl) silyl] oxy} methyl) phenyl] sulfonyl} (3-methylbutyl) amino] -10-ethyl-2 , 2,13,13-Tetramethyl-3,3-diphenyl-4-oxa-12-thionia-11-aza-3-silatetradecan-12-olate

６Ｓ，１０Ｅ）−６−［｛［４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）フェニル］スルホニル｝（３−メチルブチル）アミノ］−２，２，１３，１３−テトラメチル−３，３−ジフェニル−４−オキサ−１２−チオニア−１１−アザ−３−シラテトラデク−１０−エン−１２−オラート（１．６ｇ、１．６ｍｍｏｌ）を、無水塩化メチレン（１６ｍＬ）に溶解し、窒素雰囲気下で０℃に冷却した。攪拌溶液に臭化マグネシウムエチル（０．８２ｍＬ、２．４ｍｍｏｌ、３Ｍ溶液）を滴下して加えた。反応混合物を０℃で３時間撹拌した後、飽和塩化アンモニウム溶液で急冷した。望ましい生成物が、塩化メチレンにより二相性の系から抽出され、有機物を混合し、硫酸ナトリウム上で乾燥させ、真空内で濃縮した。粗製の油を、シリカゲルクロマトグラフィー（３００ｇ、１５から７０％酢酸エチル／ヘキサンの勾配を使用）で精製し、望ましい異性体が透明な油として得られた。望ましい異性体は、順相クロマトグラフィーにより溶出される第二の異性体であった。

6S, 10E) -6-[{[4-({[tert-butyl (diphenyl) silyl] oxy} methyl) phenyl] sulfonyl} (3-methylbutyl) amino] -2,2,13,13-tetramethyl- 3,3-diphenyl-4-oxa-12-thionia-11-aza-3-silatetradec-10-ene-12-olate (1.6 g, 1.6 mmol) was dissolved in anhydrous methylene chloride (16 mL), Cooled to 0 ° C. under nitrogen atmosphere. Magnesium ethyl bromide (0.82 mL, 2.4 mmol, 3M solution) was added dropwise to the stirring solution. The reaction mixture was stirred at 0 ° C. for 3 hours and then quenched with saturated ammonium chloride solution. The desired product was extracted from the biphasic system with methylene chloride and the organics were combined, dried over sodium sulfate and concentrated in vacuo. The crude oil was purified by silica gel chromatography (300 g, using a gradient of 15 to 70% ethyl acetate / hexanes) to give the desired isomer as a clear oil. The desired isomer was the second isomer eluted by normal phase chromatography.

Procedure J1-10: N-[(1S, 5S) -5-amino-1- (hydroxymethyl) heptyl] -4- (hydroxymethyl) -N- (3-methylbutyl) benzenesulfonamide

（６Ｓ，１０Ｓ）−６−［｛［４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）フェニル］スルホニル｝（３−メチルブチル）アミノ］−１０−エチル−２，２，１３，１３−テトラメチル−３，３−ジフェニル−４−オキサ−１２−チオニア−１１−アザ−３−シラテトラデカン−１２−オラート（１．５ｇ、１．５ｍｍｏｌ）をメタノール（１５ｍＬ）に溶解して、塩酸（３．７ｍＬ、１５ｍｍｏｌ、４Ｍ溶液）をその溶液に滴下して加えた。反応物を室温で６時間撹拌した。溶液を真空内で濃縮し、結果的に生じる粗製の油をメタノールを使用したＳＣＸを使用して精製した後、２Ｍアンモニアをメタノールに入れた溶液で望ましい化合物を溶出した。ＬＣＭＳ（Ｍ＋１）＝４０１。

(6S, 10S) -6-[{[4-({[tert-butyl (diphenyl) silyl] oxy} methyl) phenyl] sulfonyl} (3-methylbutyl) amino] -10-ethyl-2,2,13, 13-tetramethyl-3,3-diphenyl-4-oxa-12-thionia-11-aza-3-silatetradecan-12-olate (1.5 g, 1.5 mmol) was dissolved in methanol (15 mL), Hydrochloric acid (3.7 mL, 15 mmol, 4M solution) was added dropwise to the solution. The reaction was stirred at room temperature for 6 hours. The solution was concentrated in vacuo and the resulting crude oil was purified using SCX using methanol followed by elution of the desired compound with a solution of 2M ammonia in methanol. LCMS (M + 1) = 401.

Procedure J1-11: N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- ( Methoxycarbonyl) -β-phenyl-L-phenylalaninamide N-[(1S, 5S) -5-amino-1- (hydroxymethyl) heptyl] -4- (hydroxymethyl) -N- (3-methylbutyl) benzenesulfone Amide (450 mg, 1.1 mmol), N- (methoxycarbonyl) -β-phenyl-L-phenylalanine (335 mg, 1.1 mmol), EDC (237 mg, 1.2 mmol), and HOAt (43 mg, 0.3 mmol). Dissolved in DMF (11 mL) under a nitrogen atmosphere and stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate, washed with 10% potassium monohydrogen sulfate, saturated sodium bicarbonate, lithium chloride, dried over sodium sulfate and concentrated in vacuo. The crude oil was purified by silica gel chromatography (100 g, using a gradient of 70 to 100% ethyl acetate / hexanes) to give the desired product as a clear oil. ¹ H NMR (CDCl ₃ ): δ 7.8 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.4 to 7.2 (m, 10H) 6.1 (br s, 1H), 5.2 (m, 1H), 4.95 (d, J = 12 Hz, 1H), 4.85 (m, 1H), 4.75 (d, J = 12 Hz, 1 H), 4.65 (br s, 1 H), 4.4 (m, 1 H), 3.6 (s, 3 H), 3.75 (s, 2 H), 3.4 (s, 2 H) 3.3 (m, 1H), 3.0 (m, 1H), 2.6 (brs, 1H), 1.8 to 1.6 (m, 2H), 1.55 (q, J = 7.3 Hz, 2H), 1.1 to 0.8 (m, 13H), 0.7 (t, J = 7.3 Hz, 3H). LCMS (M + 1) = 682.

Example J2
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide

手順Ｊ２−１：４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−（（１Ｓ，５Ｅ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−５−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］イミノ｝ペンチル）−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド

Procedure J2-1: 4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-((1S, 5E) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl)- 5-{[(S) -tert-butylsulfinyl] imino} pentyl) -N- (3-methylbutyl) benzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−５−オキソペンチル］−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（手順Ｊ１−７、２４０ｍｇ、０．２８３ｍｍｏｌ）、Ｓ−２−メチルプロパン−２−スルフィンアミド（Ｓ−Ｅｌｌｍａｎスルホンアミド、３８ｍｇ、０．３１１ｍｍｏｌ）およびＰＰＴＳ（７ｍｇ、０．０２８ｍｍｏｌ）の溶液に、硫酸マグネシウム（３４０ｍｇ、２．８３ｍｍｏｌ）を加えた。反応混合物を室温で１６時間撹拌し、フラッシュクロマトグラフィー（シリカ、４０ｇ、０から４０％ＥｔＯＡｃ／ヘキサン）で精製して、望ましい生成物が得られた。

4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-[(1S) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5-oxopentyl] -N -(3-Methylbutyl) benzenesulfonamide (Procedure J1-7, 240 mg, 0.283 mmol), S-2-methylpropane-2-sulfinamide (S-Ellman sulfonamide, 38 mg, 0.311 mmol) and PPTS (7 mg , 0.028 mmol) was added magnesium sulfate (340 mg, 2.83 mmol). The reaction mixture was stirred at room temperature for 16 hours and purified by flash chromatography (silica, 40 g, 0 to 40% EtOAc / hexanes) to give the desired product.

Procedure J2-2: N-[(1S, 5R) -5-{[(S) -tert-butylsulfinyl] amino} -6,6,6-trifluoro-1- (hydroxymethyl) hexyl] -4- (Hydroxymethyl) -N- (3-methylbutyl) benzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−Ｎ−（（１Ｓ，５Ｅ）−１−（｛［ｔｅｒｔ−ブチル（ジフェニル）シリル］オキシ｝メチル）−５−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］イミノ｝ペンチル）−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（６０ｍｇ、０．０６３ｍｍｏｌ）をＴＨＦ（１．２ｍＬ）に入れた溶液に、トリフルオロメチルトリメチルシラン（３０μＬ、０．１９８ｍｍｏｌ）およびフッ化テトラメチルアンモニウム（３５ｍｇ、０．３７８ｍｍｏｌ）を加えた。反応混合物を室温で３日間撹拌し、調製用ＨＰＬＣで精製して、望ましい生成物が得られた。ＭＳ：Ｍ＋１＝５４５。

4-({[tert-butyl (diphenyl) silyl] oxy} methyl) -N-((1S, 5E) -1-({[tert-butyl (diphenyl) silyl] oxy} methyl) -5-{[( S) -tert-butylsulfinyl] imino} pentyl) -N- (3-methylbutyl) benzenesulfonamide (60 mg, 0.063 mmol) in THF (1.2 mL) was added to trifluoromethyltrimethylsilane (30 μL). 0.198 mmol) and tetramethylammonium fluoride (35 mg, 0.378 mmol) were added. The reaction mixture was stirred at room temperature for 3 days and purified by preparative HPLC to give the desired product. MS: M + 1 = 545.

Procedure J2-3: N-[(1S, 5R) -5-amino-6,6,6-trifluoro-1- (hydroxymethyl) hexyl] -4- (hydroxymethyl) -N- (3-methylbutyl) Benzenesulfonamide hydrochloride

Ｎ−［（１Ｓ，５Ｒ）−５−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］アミノ｝−６，６，６−トリフルオロ−１−（ヒドロキシメチル）ヘキシル］−４−（ヒドロキシメチル）−Ｎ−（３−メチルブチル）ベンゼンスルホンアミド（１２ｍｇ、０．０２２ｍｍｏｌ）をＭｅＯＨ（４４０μＬ）に入れた溶液に、４Ｎ ＨＣＬ（４ｍＬ）をジオキサンに入れたものを加えた。反応混合物を室温で９０分間撹拌し、真空内で濃縮して、望ましい生成物が得られた。ＭＳ：Ｍ＋１＝４４１。

N-[(1S, 5R) -5-{[(S) -tert-butylsulfinyl] amino} -6,6,6-trifluoro-1- (hydroxymethyl) hexyl] -4- (hydroxymethyl)- To a solution of N- (3-methylbutyl) benzenesulfonamide (12 mg, 0.022 mmol) in MeOH (440 μL) was added 4N HCL (4 mL) in dioxane. The reaction mixture was stirred at room temperature for 90 minutes and concentrated in vacuo to give the desired product. MS: M + 1 = 441.

Procedure J2-4: N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide N-[(1S, 5R) -5-amino-6,6,6-trifluoro-1- (hydroxymethyl) hexyl] -4- ( To a solution of hydroxymethyl) -N- (3-methylbutyl) benzenesulfonamide hydrochloride (10 mg, 0.023 mmol) in DMF (450 μL) was added N- (methoxycarbonyl) -β-phenyl-L-phenylalanine (6 .8 mg, 0.023 mmol), Hunig base (8 μL, 0.045 mmol) and PyBrOP (12.7 mg, .027mmol) was added. The reaction mixture was stirred at room temperature overnight, purified by preparative HPLC, and after extraction of the NaHCO ₃ basified moiety with EtOAc, the desired product N-[(1R, 5S) -6-hydroxy-5-[{[ 4- (Hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide was obtained. MS: M + 1 = 722. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.81 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.38 to 7.34 (m 4H), 7.30 to 7.10 (m, 6H), 5.06 (d, J = 11.8 Hz, 1H), 4.70 (s, 2H), 4.33 (d, J = 11 .8 Hz, 1H), 4.10 to 4.00 (m, 1H), 3.65 to 3.56 (m, 2H), 3.52 (s, 3H), 3.43 to 3.36 (m) 2H), 3.25 to 3.15 (m, 1H), 3.15 to 3.03 (m, 1H), 1.60 to 1.05 (m, 8H), 0.92 (d, J = 6.2 Hz, 6H), 0.60 to 0.45 (m, 2H).

Example J3
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3-methylbutyl) amino] hexyl} -4 -Fluoro-β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide

手順Ｊ３−１：メチルＮ−［（４−アセチルフェニル）スルホニル］−６−（ベンジルオキシ）−Ｎ−（３−メチルブチル）−Ｌ−ノルロイシナート

Procedure J3-1: Methyl N-[(4-acetylphenyl) sulfonyl] -6- (benzyloxy) -N- (3-methylbutyl) -L-norleucinate

メチルＮ−［（４−アセチルフェニル）スルホニル］−６−（ベンジルオキシ）−Ｎ−（３−メチルブチル）−Ｌ−ノルロイシナートを、メチル６−（ベンジルオキシ）−Ｌ−ノルロイシンおよび４−塩化アセチルベンゼンスルホニルから、実施例Ｊ１の調製で説明したものと類似した手順を使用して調製した。ＭＳ：Ｍ＋Ｎａ＝５２６。

Methyl N-[(4-acetylphenyl) sulfonyl] -6- (benzyloxy) -N- (3-methylbutyl) -L-norleucineate was converted to methyl 6- (benzyloxy) -L-norleucine and 4-acetylbenzene. Prepared from the sulfonyl using procedures similar to those described in the preparation of Example J1. MS: M + Na = 526.

Procedure J3-2: Methyl 6- (benzyloxy) -N-({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) -N- (3-methylbutyl) -L-norleucineate

メチルＮ−［（４−アセチルフェニル）スルホニル］−６−（ベンジルオキシ）−Ｎ−（３−メチルブチル）−Ｌ−ノルロイシナート（２．２３ｇ、４．４３ｍｍｏｌ）および（Ｒ）−２−メチル−ＣＢＳ−オキサザボロリジン（９．７４ｍＬ、９．７４ｍｍｏｌ、１Ｍ トルエン）をＴＨＦ（４４ｍＬ）に入れ、０℃に冷却した溶液に、ボランＴＨＦ錯体（３．５４ｍＬ、３．５４ｍｍｏｌ、１Ｍ ＴＨＦ）を滴下して加えた。０℃で２時間撹拌した後、ボランＴＨＦ錯体（３．５ｍＬ、３．５ｍｍｏｌ、１Ｍ ＴＨＦ）をさらに加えた。０℃でさらに４５分間撹拌した後、ＭｅＯＨおよびアセトンで反応混合物を急冷し、真空内で濃縮し、フラッシュクロマトグラフィー（１２０ｇシリカ、３５から７５％ＥｔＯＡＣ／ヘキサン）で精製し、望ましいアルコールが透明な油として得られた。ＭＳ Ｍ＋１＝５０６。その後のモッシャーエステル分析で８５：１５ジアステレオマー混合物が示された。

Methyl N-[(4-acetylphenyl) sulfonyl] -6- (benzyloxy) -N- (3-methylbutyl) -L-norleucineate (2.23 g, 4.43 mmol) and (R) -2-methyl-CBS -Oxazaborolidine (9.74 mL, 9.74 mmol, 1 M toluene) was added to THF (44 mL), and borane THF complex (3.54 mL, 3.54 mmol, 1 M THF) was added dropwise to the solution cooled to 0 ° C. And added. After stirring for 2 hours at 0 ° C., borane THF complex (3.5 mL, 3.5 mmol, 1M THF) was further added. After stirring at 0 ° C. for an additional 45 minutes, the reaction mixture is quenched with MeOH and acetone, concentrated in vacuo, purified by flash chromatography (120 g silica, 35 to 75% EtOAC / hexanes), and the desired alcohol is clear. Obtained as an oil. MS M + 1 = 506. Subsequent Moscher ester analysis indicated an 85:15 diastereomeric mixture.

Procedure J3-3: N-[(1S) -5- (benzyloxy) -1- (hydroxymethyl) pentyl] -4-[(1S) -1-hydroxyethyl] -N- (3-methylbutyl) benzenesulfone Amide

メチル６−（ベンジルオキシ）−Ｎ−（｛４−［（１Ｓ）−１−ヒドロキシエチル］フェニル｝−スルホニル）−Ｎ−（３−メチルブチル）−Ｌ−ノルロイシナート（２．１５ｇ、４．２５ｍｍｏｌ）をＴＨＦ（１４ｍＬ）に入れた溶液に、水素化ホウ素リチウム（１０．６ｍＬ、２１．３ｍｍｏｌ、２Ｍ ＴＨＦ）を徐々に加えた。室温で４時間撹拌した後、反応混合物を０℃まで冷やし、ＭｅＯＨおよびＥｔＯＡｃで急冷し、室温まで温め、ＥｔＯＡｃおよび５０ｍＬ １Ｎ ＮａＯＨで希釈した。１０分間激しく撹拌した後、有機層を分離し、ブラインで洗浄し、硫酸ナトリウム上で乾燥させ、真空内で濃縮して、望ましい生成物が油として得られた。ＭＳ Ｍ＋Ｎａ＝５００。

Methyl 6- (benzyloxy) -N-({4-[(1S) -1-hydroxyethyl] phenyl} -sulfonyl) -N- (3-methylbutyl) -L-norleucineate (2.15 g, 4.25 mmol) Was added to THF (14 mL) and lithium borohydride (10.6 mL, 21.3 mmol, 2M THF) was slowly added. After stirring at room temperature for 4 hours, the reaction mixture was cooled to 0 ° C., quenched with MeOH and EtOAc, warmed to room temperature, and diluted with EtOAc and 50 mL 1N NaOH. After stirring vigorously for 10 minutes, the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the desired product as an oil. MS M + Na = 500.

Procedure J3-4 to J3-10: N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3 -Methylbutyl) amino] hexyl} -4-fluoro- [beta]-(4-fluorophenyl) -N [alpha]-(methoxycarbonyl) -L-phenylalaninamide N-{(1R, 5S) -1-cyclopropyl-6-hydroxy- 5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3-methylbutyl) amino] hexyl} -4-fluoro-β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide is converted to N-[(1S) -5- (benzyloxy) -1- (hydroxymethyl) pentyl] -4-[(1S) -1-hydride. Xylethyl] -N- (3-methylbutyl) benzenesulfonamide, TBDPS-Cl, (R)-(+)-tert-butanesulfinamide, cyclopropylmagnesium bromide and 4-fluoro-β- (4-fluorophenyl)- Prepared from N- (methoxycarbonyl) -L-phenylalanine using a procedure similar to that described in Procedure J1-5 to J1-11 of Example J1. MS M + 1 = 744. ¹ H NMR (d ₄ MeOH): δ 7.81 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.40 to 7.28 (m, 4H ), 7.05 to 6.95 (m, 4H), 4.95 to 4.80 (m, 2H), 4.31 (d, J = 11.9 Hz, 1H), 3.72 to 3.62 (M, 1H), 3.54 (s, 3H), 3.48 to 3.36 (m, 2H), 3.24 to 3.03 (m, 2H), 2.94 to 2.84 (m 1H), 1.60 to 0.65 (m, 10H), 1.45 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.2 Hz, 6H), 0.45 To 0.30 (m, 2H), 0.21 to 0.04 (m, 2H).

The following examples (Table J) show suitable basic elements (MeO ₂ C—Ph—SO ₂ Cl or MeCO—Ph—SO ₂ Cl, R ⁵ MgX or CF ₃ TMS, R ¹ OH, HO ₂ C—CHR. ^6- NHR ⁷ or the corresponding active amino acid such as hydroxy succinate), and was made using a procedure similar to that described in the preparation of Examples J1 to J3. In some cases, NHR ⁷ was protected as Boc, but the last procedure required acidic Boc removal.

Example K1
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide

手順Ｋ１−１ エチル−２−アミノペンタ−４−エン酸塩酸塩
この中間体の合成は、実施例Ｆ１−１で説明したものと類似した方法で調製したが、溶剤としてメタノールを使用するという変更をした。

Procedure K1-1 Ethyl-2-aminopent-4-enoic acid hydrochloride The synthesis of this intermediate was prepared in a manner similar to that described in Example F1-1, except that methanol was used as the solvent. Did.

Procedure K1-2 Methyl 4- (N- (1-methoxy-1-oxopent-4-en-2-yl) sulfamoyl) benzoate

エチル（２Ｓ）−２−アミノ−４−ペンテン酸塩塩酸塩（１２．０１ｇ、６６．９ｍｍｏｌ）を２２３ｍＬ ＣＨ_２Ｃｌ_２に入れた溶液に、トリエチルアミン（２０．０ｍＬ、１４０ｍｍｏｌ）および４−塩化カルボメトキシフェニルスルホニル（１４．６７ｇ、６６．２ｍｍｏｌ）を加えた。反応を室温で１６時間進行させた後、ＥＡで希釈し、０．５Ｍ ＨＣｌ（２ｘ）、飽和ＮａＨＣＯ_３水溶液およびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、濾過し、濃縮させて、望ましい生成物が得られたが、これをそれ以上精製することなく使用した。

To a solution of ethyl (2S) -2-amino-4-pentenoate hydrochloride (12.01 g, 66.9 mmol) in 223 mL CH ₂ Cl ₂ was added triethylamine (20.0 mL, 140 mmol) and 4-chlorochloride. Methoxyphenylsulfonyl (14.67 g, 66.2 mmol) was added. The reaction was allowed to proceed at room temperature for 16 h before being diluted with EA, washed with 0.5 M HCl (2 ×), saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated, The desired product was obtained and used without further purification.

Procedure K1-3 Methyl 4-({Isopropyl [(1S-1- (methoxycarbonyl) -3-buten-1-yl] amino) sulfonyl) benzoate

メチル４−（Ｎ−（１−メトキシ）−１−オキソペンタン−４−エン−２−イル）スルホニル）安息香酸塩（１．９７ｇ、５．７７ｍｍｏｌ）を３０ｍＬ ＴＨＦに入れた溶液に、Ｐｈ_３Ｐ（３．０３ｇ、１１．５４ｍｍｏｌ）、ｉ−ＰｒＯＨ（１．７３ｇ、２８．９ｍｍｏｌ）およびＤＩＡＤ（２．２４ｍＬ、１１．５ｍｍｏｌ）を加えた。夜通し撹拌した後、反応混合物を濃縮し、残留物をシリカゲルクロマトグラフィー（勾配：２０から１００％ＥＡ／ヘキサン）で精製して、望ましい生成物が得られた。ＭＳ（Ｍ＋Ｈ＝３８３）。

To a solution of methyl 4- (N- (1-methoxy) -1-oxopentan-4-en-2-yl) sulfonyl) benzoate (1.97 g, 5.77 mmol) in 30 mL THF was added Ph _3. P (3.03 g, 11.54 mmol), i-PrOH (1.73 g, 28.9 mmol) and DIAD (2.24 mL, 11.5 mmol) were added. After stirring overnight, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (gradient: 20 to 100% EA / hexanes) to give the desired product. MS (M + H = 383).

Procedure K1-4 4- (hydroxymethyl) -N-[(1S-1- (hydroxymethyl) -3-buten-1-yl] -N-isopropylbenzenesulfonamide

メチル４−（｛イソプロピル［（１Ｓ−１−（メトキシカルボニル）−３−ブテン−１−イル］アミノ）スルホニル）安息香酸塩（５．６４ｇ、１５．２７ｍｍｏｌ）および５１ｍＬ無水ＴＨＦを含む攪拌溶液を、０℃に冷却し、不活性環境（窒素）下で維持した。冷却した溶液に、３０．５ｍＬ ＬｉＡｌＨ_４（ＴＨＦ中１Ｍ、３０．５ｍｍｏｌ）を注射器で加えた。結果として生じる混合物を０℃で３０分間撹拌した。反応混合物に１５ｍＬ ４Ｎ ＨＣｌを加え、結果として生じる混合物を均質になるまで撹拌した。ＥｔＯＡｃを酸性化した反応混合物に加え、有機層を水層から分離した。有機物をブラインで洗浄し、およびＮａ_２ＳＯ_４上で乾燥させ、ジオールが得られたが、これをそれ以上精製することなく次の手順で使用した。ＭＳ（Ｍ＋１＝３１４）。

A stirred solution containing methyl 4-({isopropyl [(1S-1- (methoxycarbonyl) -3-buten-1-yl] amino) sulfonyl) benzoate (5.64 g, 15.27 mmol) and 51 mL anhydrous THF. , Cooled to 0 ° C. and maintained under an inert environment (nitrogen). To the cooled solution, 30.5 mL LiAlH ₄ (1M in THF, 30.5 mmol) was added via syringe. The resulting mixture was stirred at 0 ° C. for 30 minutes. To the reaction mixture was added 15 mL 4N HCl and the resulting mixture was stirred until homogeneous. EtOAc was added to the acidified reaction mixture and the organic layer was separated from the aqueous layer. The organics were washed with brine and dried over Na ₂ SO ₄ to give the diol, which was used in the next procedure without further purification. MS (M + 1 = 314).

Procedure K1-5 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S-1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -3-butene -1-yl] -N-isopropylbenzenesulfonamide

４−（ヒドロキシメチル）−Ｎ−［（１Ｓ−１−（ヒドロキシメチル）−３−ブテン−１−イル］−Ｎ−イソプロピルベンゼンスルホンアミド（４．５ｇ、１４．３６ｍｍｏｌ）および１５ｍＬ無水ＤＣＭを含む溶液に、ｔｅｒｔ−塩化ブチルジメチル（６．４９ｇ、４３．１ｍｍｏｌ）、イミダゾール（２．９３ｇ、４３．１ｍｍｏｌ）、およびＤＭＡＰ（３．５１ｇ、２８．７ｍｍｏｌ）を順番に加えた。結果として生じる溶液を室温で１２時間撹拌した。反応混合物を真空下で濃縮して、クロマトグラフィー（勾配：２０％から５０％酢酸エチル／ヘキサン）で分離して、ベンジルシリルエーテルが得られた。ＭＳ（Ｍ＋１＝５４２）。

Contains 4- (hydroxymethyl) -N-[(1S-1- (hydroxymethyl) -3-buten-1-yl] -N-isopropylbenzenesulfonamide (4.5 g, 14.36 mmol) and 15 mL anhydrous DCM. To the solution was added tert-butyldimethylchloride (6.49 g, 43.1 mmol), imidazole (2.93 g, 43.1 mmol), and DMAP (3.51 g, 28.7 mmol) in order. The reaction mixture was concentrated in vacuo and separated by chromatography (gradient: 20% to 50% ethyl acetate / hexanes) to give the benzyl silyl ether, MS (M + 1 = 542).

Procedure K1-6 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 3S) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl)- 5-oxo-3-penten-1-yl] -N-isopropylbenzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ−１−１（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ）メチル）−３−ブテン−１−イル］−Ｎ−イソプロピルベンゼンスルホンアミド（４．３０ｇ、５．４４ｍｍｏｌ）、クロトンアルデヒド（４ｍＬ、３．３８ｇ、４８．３ｍｍｏｌ）を７５ｍＬ ＤＣＭに入れた攪拌溶液に、グラブス第二世代触媒（０．２３１ｇ、０．２７２ｍｍｏｌ）を加えた。還流冷却器を、同様にＮ_２入口を持つ反応槽に取り付けた。反応混合物をシリコーン油浴内で窒素下で３０分間加熱して還流させ、室温まで冷ました。次に、反応混合物を真空下で濃縮し、クロマトグラフィー（勾配：２０％から１００％酢酸エチル／ヘキサン）で分離して、エナールが得られた。

4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S-1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -3-buten-1-yl ] To a stirred solution of -N-isopropylbenzenesulfonamide (4.30 g, 5.44 mmol), crotonaldehyde (4 mL, 3.38 g, 48.3 mmol) in 75 mL DCM was added Grubbs second generation catalyst (0.231 g). 0.272 mmol) was added. A reflux condenser was also attached to the reaction vessel with an N ₂ inlet. The reaction mixture was heated to reflux in a silicone oil bath for 30 minutes under nitrogen and cooled to room temperature. The reaction mixture was then concentrated under vacuum and separated by chromatography (gradient: 20% to 100% ethyl acetate / hexanes) to give the enal.

Procedure K1-7 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 3S) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl)- 5-oxo-3-pentyl] -N-isopropylbenzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ，３Ｓ）−１−１（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ）メチル）−５−オキソ−３−ペンテン−１−イル］−Ｎ−イソプロピルベンゼンスルホンアミド（３．００ｇ、５．４２ｍｍｏｌ）を２８．６ｍＬ酢酸エチルに入れたものを含む溶液に、１０％Ｐｄ／Ｃ（０．５７９ｇ、０．５４４ｍｍｏｌ）を加えた。結果として生じる混合物をＳＴＰ下で１．５時間水素化した。次に、反応混合物をセライトを通過させて濾過し、真空下で濃縮して、アルデヒドが得られた。

4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 3S) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -5-oxo- To a solution containing 3-penten-1-yl] -N-isopropylbenzenesulfonamide (3.00 g, 5.42 mmol) in 28.6 mL ethyl acetate, 10% Pd / C (0.579 g, 0 .544 mmol) was added. The resulting mixture was hydrogenated under STP for 1.5 hours. The reaction mixture was then filtered through celite and concentrated in vacuo to give the aldehyde.

Procedure K1-8 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 5E) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl)- 5-{[(S) -tert-butylsulfinyl] imino) pentyl) -N-isopropylbenzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ，３Ｓ）−１−１（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ）メチル）−５−オキソ−３−ペンチル］−Ｎ−イソプロピルベンゼンスルホンアミド（３．０１ｇ、５．４２ｍｍｏｌ）を１３．５ｍＬ無水ＤＣＭに入れたものを含む溶液に、ＭｇＳＯ_４（３．２６ｇ、２７．１ｍｍｏｌ）、（Ｓ）−Ｅｌｌｍａｎスルフィンアミン（０．９８５ｇ、８．１３ｍｍｏｌ）、およびピリジニウムｐ−トルエンスルホナート（０．１３６ｇ、０．５４２ｍｍｏｌ）を順番に加えた。結果として生じる混合物を室温で１８時間撹拌した。次に、反応混合物を真空下で濃縮し、クロマトグラフィー（勾配：１０％から８０％ＥｔＯＡｃ／ヘキサン）で分離して、スルフィンイミンが得られた。ＭＳ（Ｍ＋１＝６７６）。

4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 3S) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -5-oxo- To a solution containing 3-pentyl] -N-isopropylbenzenesulfonamide (3.01 g, 5.42 mmol) in 13.5 mL anhydrous DCM was added MgSO ₄ (3.26 g, 27.1 mmol), (S). -Ellman sulfinamine (0.985 g, 8.13 mmol) and pyridinium p-toluenesulfonate (0.136 g, 0.542 mmol) were added in turn. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and separated by chromatography (gradient: 10% to 80% EtOAc / hexanes) to give the sulfinimine. MS (M + 1 = 676).

Procedure K1-9 4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 5E) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl)- 5-{[(S) -tert-butylsulfinyl] amino) hexyl) -N-isopropylbenzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ，５Ｅ）−１−１（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ）メチル）−５−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］イミノ）ペンチル）−Ｎ−イソプロピルベンゼンスルホンアミド（２．４０ｇ、３．５５ｍｍｏｌ）を４０ｍＬ ＤＣＭに入れた溶液を０℃に冷却し、窒素雰囲気下で維持した。この冷却した溶液に、臭化マグネシウムメチル（２．３７ｍＬ、７．１１ｍｍｏｌ、ジエチルエーテル中３．０Ｍ）を注射器で滴下して加えた。反応混合物を１８時間撹拌したが、その時点で、ＴＬＣによる判断で反応は完了していた。反応混合物を飽和ＮＨ_４Ｃｌ溶液で希釈し、ＤＣＭ（３ｘ１０ｍＬ）で抽出した。混合した有機物をＮａ_２ＳＯ_４上で乾燥させて、スルフィンアミンが得られたが、これをそのまま次の手順で使用した。

4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 5E) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -5-{[ A solution of (S) -tert-butylsulfinyl] imino) pentyl) -N-isopropylbenzenesulfonamide (2.40 g, 3.55 mmol) in 40 mL DCM was cooled to 0 ° C. and maintained under a nitrogen atmosphere. To this cooled solution, magnesium methyl bromide (2.37 mL, 7.11 mmol, 3.0 M in diethyl ether) was added dropwise via a syringe. The reaction mixture was stirred for 18 hours, at which point the reaction was complete as judged by TLC. The reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with DCM (3 × 10 mL). The combined organics were dried over Na ₂ SO ₄ to give sulfinamine, which was used as such in the next procedure.

Procedure K1-10 N-[(1S, 5S) -5-amino-1- (hydroxymethyl) hexyl] -4- (hydroxylmethyl) -N-isopropylbenzenesulfonamide

４−（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ｝メチル）−Ｎ−［（１Ｓ，５Ｅ）−１−１（｛［ｔｅｒｔ−ブチル（ジメチル）シリル］オキシ）メチル）−５−｛［（Ｓ）−ｔｅｒｔ−ブチルスルフィニル］アミノ）ヘキシル）−Ｎ−イソプロピルベンゼンスルホンアミド（２．４０ｇ、３．４７ｍｍｏｌ）を６．０ｍＬメタノールに入れた溶液に、２Ｍ ＨＣｌをジオキサンに入れたもの（１０．４２ｍＬ、２０．８３ｍｍｏｌ）を加え、その混合物を室温で１８時間撹拌した。次に、反応混合物を真空下で濃縮し、強陽イオン交換クロマトグラフィー（ＳＣＸ）で分離して、アミン−ジオールが得られた。ＭＳ（Ｍ＋１＝３５９）。

4-({[tert-butyl (dimethyl) silyl] oxy} methyl) -N-[(1S, 5E) -1-1 ({[tert-butyl (dimethyl) silyl] oxy) methyl) -5-{[ (S) -tert-butylsulfinyl] amino) hexyl) -N-isopropylbenzenesulfonamide (2.40 g, 3.47 mmol) in 6.0 mL methanol and 2M HCl in dioxane (10 .42 mL, 20.83 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under vacuum and separated by strong cation exchange chromatography (SCX) to give the amine-diol. MS (M + 1 = 359).

Procedure K1-11 N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -N-α- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide N-[(1S, 5S) -5-amino-1- (hydroxymethyl) hexyl] -4- (hydroxylmethyl) -N-isopropylbenzenesulfonamide (1.80 g , 4.56 mmol) in 4 mL THF and to a solution containing 4 mL saturated NaHCO ₃ solution, methyl [(1S) -2-[(2,5-dioxo-1-pyrrolidinyl) oxy] -1- ( Diphenylmethyl) -2-oxoethyl] carbamate (1.81 g, 4.56 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was diluted with water and ethyl acetate, and the organic and aqueous layers were separated. After organics were collected and dried over Na ₂ SO _4, filtered, and concentrated in vacuo, and purified by reverse phase chromatography, the desired product was obtained. Purification reveals a 10: 1 mixture of diastereomers, favoring the desired diastereomers. MS (M + 1 = 640). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.35-7.18 (m, 10H ), 6.07 (br s, 1H), 5.18 (d, J = 9.2 Hz, 1H), 4.92 to 4.71 (m, 3H), 4.53 (br s, 1H), 4.38 (d, J = 7 Hz, 1H) 3.59 (s, 3H), 3.53 to 3.49 (m, 4H), 3.29 (br s, 1H), 2.83 (br s) 1H), 2.89 to 2.60 (br s, 1H), 1.63 to 1.51 (m, 3H) 1.40 to 1.33 (m, 3H), 0.89 (m, 2H) ), 0.74 (d, J = 6.8 Hz, 2H).

Example K2
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) -amino] hexyl} -Nα- ( Methoxycarbonyl) -β-phenyl-L-phenylalaninamide

手順Ｋ２−１ エチル（２Ｓ）−２−アミノ−４−ペンテン酸塩塩酸塩

Procedure K2-1 Ethyl (2S) -2-amino-4-pentenoate hydrochloride

  The compound was prepared as described in Procedure F1-1 of Example F1.

Procedure K2-2 Ethyl (2S) -2-{[(4-acetylphenyl) sulfonyl] amino} -4-pentenoate

エチル（２Ｓ）−２−アミノ−４−ペンテン酸塩塩酸塩Ｋ２−１（２ｇ、１１．１３ｍｍｏｌ）を１１１ｍＬ ＤＣＭに入れた溶液に、４−塩化アセチルベンゼンスルホニル（２．１９ｇ、１０．０２ｍｍｏｌ）およびトリエチルアミン（１．５４ｍＬ、１１．１３ｍｍｏｌ）を加えた。次に溶液を室温で１８時間攪拌した。反応混合物を飽和ＮａＨＣＯ_３溶液およびブラインで３回洗浄した。有機物をＮａ_２ＳＯ_４上で乾燥させ、クロマトグラフィー（勾配：２０％−５０％ＥｔＯＡｃ／ヘキサン）で分離して、ケトンＫ２−２が得られた。ＬＣ／ＭＳ（Ｍ＋１＝３２６）。

To a solution of ethyl (2S) -2-amino-4-pentenoate hydrochloride K2-1 (2 g, 11.13 mmol) in 111 mL DCM was added 4-acetylbenzenesulfonyl chloride (2.19 g, 10.02 mmol). And triethylamine (1.54 mL, 11.13 mmol) were added. The solution was then stirred at room temperature for 18 hours. The reaction mixture was washed 3 times with saturated NaHCO ₃ solution and brine. The organics were dried over Na ₂ SO ₄ and separated by chromatography (gradient: 20% -50% EtOAc / hexanes) to give ketone K2-2. LC / MS (M + 1 = 326).

Procedure K2-3 ethyl- (2S) -2-[{4-[(1S))-1-hydroxyethyl] phenyl} sulfonyl) amino] -4-pentenoate

Ｋ２−２スルホンアミド（１．８８ｇ、５．８０ｍｍｏｌ）を５８ｍＬ無水ＴＨＦに入れた溶液を０℃まで冷却し、窒素雰囲気下で保持した。この溶液に、（Ｒ）−（＋）−２−メチル−ＣＢＳ−オキサザボロリジン（１２．７５ｍＬ、１２．７５ｍｍｏｌ、トルエン中１Ｍ）を注射器で加えた。結果として生じる溶液を０℃で３０分間撹拌し、その後でボラン−ＴＨＦ錯体（４．６４ｍＬ、４．６４ｍｍｏｌ、ＴＨＦ中１Ｍ）を注射器で滴下して加えた。結果として生じる溶液を０℃で２時間、ＴＬＣで判断して反応が完了するまで撹拌した。反応混合物をアセトンおよびメタノールを加えて急冷した。反応混合物を真空下で濃縮して、クロマトグラフィー（勾配：２０％から１００％酢酸エチル／ヘキサン）で分離して、望ましい化合物Ｋ２−３が得られた。ＬＣ／ＭＳ（Ｍ＋２３＝３５０）。ジアステレオ異性的な純度を、モッシャーエステル分析により、下記の手順Ｋ２−４に記載した手順に従い確定した。

A solution of K2-2sulfonamide (1.88 g, 5.80 mmol) in 58 mL anhydrous THF was cooled to 0 ° C. and kept under a nitrogen atmosphere. To this solution was added (R)-(+)-2-methyl-CBS-oxazaborolidine (12.75 mL, 12.75 mmol, 1M in toluene) via syringe. The resulting solution was stirred at 0 ° C. for 30 minutes, after which borane-THF complex (4.64 mL, 4.64 mmol, 1M in THF) was added dropwise via syringe. The resulting solution was stirred at 0 ° C. for 2 hours until the reaction was complete as judged by TLC. The reaction mixture was quenched by adding acetone and methanol. The reaction mixture was concentrated in vacuo and separated by chromatography (gradient: 20% to 100% ethyl acetate / hexanes) to give the desired compound K2-3. LC / MS (M + 23 = 350). Diastereoisomeric purity was determined by Moscher ester analysis according to the procedure described in Procedure K2-4 below.

Procedure K2-4 Ethyl- (2S) -2-({[4-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] sulfonyl} amino) -4-pentenoate

１００ｍｇベンジルアルコールＫ２−３および３．０５ｍＬ無水ＤＣＭを含む溶液に、５９．７ｍｇの４−ジメチルアミノピリジンおよび１０８ｍｇのＲ−モッシャー酸塩化物（すなわち、α−塩化メトキシトリフルオロフェニルアセチル）を加えた。次に溶液を室温で１５時間攪拌した。粗製の反応混合物をＬＣ／ＭＳ（Ｍ＋２３＝５４６）で分析した。ジアステレオマー比＞１０：１が、^１Ｈ ＮＭＲを使用して観察された。

To a solution containing 100 mg benzyl alcohol K2-3 and 3.05 mL anhydrous DCM was added 59.7 mg 4-dimethylaminopyridine and 108 mg R-Mosher acid chloride (ie, α-methoxytrifluorotrifluorophenylacetyl chloride). . The solution was then stirred at room temperature for 15 hours. The crude reaction mixture was analyzed by LC / MS (M + 23 = 546). A diastereomeric ratio> 10: 1 was observed using ¹ H NMR.

Procedure K2-5 Ethyl (2S) -2-({[4-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] sulfonyl} amino) -4-pentenoate

ベンジルアルコールＫ２−３（１．９２ｇ、５．８６ｍｍｏｌ）を５８．３ｍＬ無水ＤＣＭに入れた溶液に、ｔｅｒｔ−ブチルジメチルシリル塩化物（１．３２ｇ、８．７８ｍｍｏｌ）、イミダゾール（７９７ｍｇ、１１．７１ｍｍｏｌ）、および４−ジメチルアミノピリジン（１．４３ｇ、１１．７１ｍｍｏｌ）を順番に加えた。結果として生じる溶液を室温で１２時間撹拌した。反応混合物を真空下で濃縮して、クロマトグラフィー（勾配：２０％から５０％酢酸エチル／ヘキサン）で分離して、ベンジルシリルエーテルＫ２−５が得られた。ＬＣ／ＭＳ（Ｍ＋２３＝４６４）。

To a solution of benzyl alcohol K2-3 (1.92 g, 5.86 mmol) in 58.3 mL anhydrous DCM was added tert-butyldimethylsilyl chloride (1.32 g, 8.78 mmol), imidazole (797 mg, 11.71 mmol). ), And 4-dimethylaminopyridine (1.43 g, 11.71 mmol) were added in turn. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and separated by chromatography (gradient: 20% to 50% ethyl acetate / hexanes) to give benzylsilyl ether K2-5. LC / MS (M + 23 = 464).

Procedure K2-6 ethyl (2S) -2-({[4-((1R) -1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N-isopropylphenyl] sulfonyl} amino) -4 -Pentenoate

ベンジルシリルエーテルＫ２−５（１．９２ｇ、４．３５ｍｍｏｌ）を４３．５ｍＬ無水ＴＨＦに入れた溶液に、無水２−プロパノール（２．０１ｍＬ、２６．１ｍｍｏｌ）、トリフェニルホスフィン（２．８５ｇ、１０．８７ｍｍｏｌ）およびジイソプロピルアゾジカルボン酸塩（２．１９８ｇ、１０．８７ｍｍｏｌ）を順番に加えた。結果として生じる混合物を室温で１２時間撹拌した。次に、反応混合物を加圧下で濃縮し、クロマトグラフィー（勾配：０％から６５％酢酸エチル／ヘキサン）で分離して、ベンジルシリルエーテルＫ２−６が得られた。ＬＣ／ＭＳ（Ｍ＋１＝４８４）。

To a solution of benzylsilyl ether K2-5 (1.92 g, 4.35 mmol) in 43.5 mL anhydrous THF, anhydrous 2-propanol (2.01 mL, 26.1 mmol), triphenylphosphine (2.85 g, 10 .87 mmol) and diisopropyl azodicarboxylate (2.198 g, 10.87 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under pressure and separated by chromatography (gradient: 0% to 65% ethyl acetate / hexane) to give benzylsilyl ether K2-6. LC / MS (M + 1 = 484).

Procedure K2-7 4-((S) -1-hydroxyethyl) -N-((S) -1-hydroxypent-4-en-2-yl) -N-isopropylbenzenesulfonamide

Ｋ２−６（２．１１ｇ、４．３６ｍｍｏｌ）を４３．６ｍＬ無水ＴＨＦに入れた溶液を、不活性環境（窒素）下で０℃に冷却し、その後でＬｉＡｌＨ_４（ＴＨＦ中１Ｍ、８．７２ｍＬ、８．７２ｍｍｏｌ）を注射器で加えた。結果として生じる混合物を０℃で３０分間撹拌した。反応混合物に、５ｍＬ １Ｎ ＨＣｌを混合物が凝固するまで加え、５ｍＬの濃ＨＣｌを反応混合物が均質になるまで加えた。酸性化した反応混合物に酢酸エチルを加えた。有機層を水層から分離した。有機物をブラインで洗浄し、およびＮａ_２ＳＯ_４上で乾燥させて、ジオールＫ２−７が得られた。この物質をそれ以上精製することなく手順Ｋ２−８で使用した。

A solution of K2-6 (2.11 g, 4.36 mmol) in 43.6 mL anhydrous THF was cooled to 0 ° C. under an inert environment (nitrogen) followed by LiAlH ₄ (1M in THF, 8.72 mL). , 8.72 mmol) was added via syringe. The resulting mixture was stirred at 0 ° C. for 30 minutes. To the reaction mixture was added 5 mL 1N HCl until the mixture solidified and 5 mL of concentrated HCl was added until the reaction mixture was homogeneous. Ethyl acetate was added to the acidified reaction mixture. The organic layer was separated from the aqueous layer. The organics were washed with brine and dried over Na ₂ SO ₄ to give diol K2-7. This material was used in Procedure K2-8 without further purification.

Procedure K2-8 4-((S) -1- (tert-butyldimethylsilyloxy) ethyl) -N-((S) -1- (tert-butyldimethylsilyloxy) pent-4-en-2-yl ) -N-isopropylbenzenesulfonamide

ベンジルアルコールＫ２−７（１．９３ｇ、５．８６ｍｍｏｌ）を５８．９ｍＬ無水ＤＣＭに入れた溶液に、ＴＢＳ塩化物（２．２２ｇ、１４．７１ｍｍｏｌ）、イミダゾール（０．８０１ｍｇ、１１．７７ｍｍｏｌ）、およびＤＭＡＰ（１．４３８ｇ、１１．７７ｍｍｏｌ）を順番に加えた。結果として生じる溶液を室温で１２時間撹拌した。反応混合物を真空下で濃縮して、クロマトグラフィー（勾配：２０％から５０％ＥｔＯＡｃ／ヘキサン）で分離して、ベンジルシリルエーテルＫ２−８が得られた。ＬＣ／ＭＳ（Ｍ＋２３＝４６４）。

To a solution of benzyl alcohol K2-7 (1.93 g, 5.86 mmol) in 58.9 mL anhydrous DCM was added TBS chloride (2.22 g, 14.71 mmol), imidazole (0.801 mg, 11.77 mmol), And DMAP (1.438 g, 11.77 mmol) were added sequentially. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and separated by chromatography (gradient: 20% to 50% EtOAc / hexanes) to give the benzyl silyl ether K2-8. LC / MS (M + 23 = 464).

Procedure K2-9 N-((S, E) -1- (tert-butyldimethylsilyloxy) -6-oxohex-4-en-2-yl) -4-((S) -1- (tert-butyl Dimethylsilyloxy) ethyl) -N-isopropylbenzenesulfonamide

シリルエーテルＫ２−８（１．８２ｇ、３．２７ｍｍｏｌ）、クロトンアルデヒド（２．２９ｇ、３２．７ｍｍｏｌ）を２５ｍＬ ＤＣＭに入れた溶液に、０．２７７ｇのグラブス第二世代触媒を加えた。還流冷却器を、同様にＮ_２入口を持つ反応槽に取り付けた。反応混合物をシリコーン油浴内で窒素下で３０分間加熱して還流させ、室温まで冷ました。次に、反応混合物を真空下で濃縮し、クロマトグラフィー（勾配：２０％から１００％酢酸エチル／ヘキサン）で分離して、エナールＫ２−９が得られた。

To a solution of silyl ether K2-8 (1.82 g, 3.27 mmol), crotonaldehyde (2.29 g, 32.7 mmol) in 25 mL DCM was added 0.277 g of Grubbs second generation catalyst. A reflux condenser was also attached to the reaction vessel with an N ₂ inlet. The reaction mixture was heated to reflux in a silicone oil bath for 30 minutes under nitrogen and cooled to room temperature. The reaction mixture was then concentrated under vacuum and separated by chromatography (gradient: 20% to 100% ethyl acetate / hexane) to give enal K2-9.

Procedure K2-10 N-((S, E) -1- (tert-butyldimethylsilyloxy) -6-oxohexane-2-yl) -4-((S) -1- (tert-butyldimethylsilyloxy) ) Ethyl) -N-isopropylbenzenesulfonamide

エナールＫ２−９（１．６６ｇ、２．８６ｍｍｏｌ）を２８．６ｍＬ酢酸エチルに入れた溶液に、１０％Ｐｄ／Ｃ（３４０ｍｇ、０．２８６ｍｍｏｌ）を加えた。結果として生じる混合物をＳＴＰ下で１時間水素化した。反応混合物をセライトを通過させて濾過し、真空下で濃縮し、アルデヒドＫ２−１０が得られた。

To a solution of Enal K2-9 (1.66 g, 2.86 mmol) in 28.6 mL ethyl acetate was added 10% Pd / C (340 mg, 0.286 mmol). The resulting mixture was hydrogenated under STP for 1 hour. The reaction mixture was filtered through celite and concentrated in vacuo to give aldehyde K2-10.

Procedure K2-11 4-((1) -1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N-((1S, 5E) -1-({[tertbutyl (dimethyl) silyl] oxy } Methyl) -5-{[(R) -tert-butylsulfinyl] imino} pentyl) -N-isopropylbenzenesulfonamide

Ｋ２−１０（１．５８８ｇ）を１３．５ｍＬ無水ＤＣＭに入れた溶液に、ＭｇＳＯ_４（１．６３ｇ、１３．５５ｍｍｏｌ）、（Ｒ）−Ｅｌｌｍａｎスルフィンアミン（４９３ｍｇ、４．０６ｍｍｏｌ）、およびＰＰＴＳ（６８ｍｇ、０．２７１ｍｍｏｌ）を順番に加えた。結果として生じる混合物を室温で１８時間撹拌した。反応混合物を真空下で濃縮し、クロマトグラフィー（１０％から８０％ＥｔＯＡｃ／ヘキサン）で分離して、スルフィンイミンＫ２−１１が得られた。ＬＣ／ＭＳ（Ｍ＋１＝６９０）。

To a solution of K2-10 (1.588 g) in 13.5 mL anhydrous DCM was added MgSO ₄ (1.63 g, 13.55 mmol), (R) -Ellman sulfinamine (493 mg, 4.06 mmol), and PPTS ( 68 mg, 0.271 mmol) was added in order. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and separated by chromatography (10% to 80% EtOAc / hexane) to give sulfinimine K2-11. LC / MS (M + 1 = 690).

Procedure K2-12 4-((1S) -1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N-((1S, 5S) -1-({[tert-butyl (dimethyl) silyl] Oxy} methyl) -5-{[(R) -tert-butylsulfinyl] amino} heptyl) -N-isopropylbenzenesulfonamide

スルフィンイミンＫ２−１１（４８５ｍｇ、０．７０４ｍｍｏｌ）を７ｍＬ ＤＣＭに入れた溶液を、０℃まで冷却し、窒素雰囲気下で維持した。この冷却した溶液にエチルマグネシウムブロミド（０．４６９ｍＬ、１．４０７ｍｍｏｌ、ジエチルエーテル中３．０Ｍ）を注射器で滴下して加えた。撹拌中の反応混合物を室温まで１８時間温めたが、その時点でＴＬＣによる判断で反応は完了していた。反応混合物を飽和ＮＨ_４Ｃｌ溶液で希釈し、ＤＣＭ（３ｘ１０ｍＬ）で抽出した。混合した有機物をＮａ_２ＳＯ_４上で乾燥させて、スルフィンアミン Ｋ２−１２が得られた。

A solution of sulfinimine K2-11 (485 mg, 0.704 mmol) in 7 mL DCM was cooled to 0 ° C. and maintained under a nitrogen atmosphere. To this cooled solution was added ethylmagnesium bromide (0.469 mL, 1.407 mmol, 3.0 M in diethyl ether) dropwise with a syringe. The stirring reaction mixture was warmed to room temperature for 18 hours, at which point the reaction was complete as judged by TLC. The reaction mixture was diluted with saturated NH ₄ Cl solution and extracted with DCM (3 × 10 mL). The combined organics were dried over Na ₂ SO ₄ to give sulfinamine K2-12.

Procedure K2-13 N- (1S, 5S) -5-amino-1- (hydroxymethyl) heptyl] -4-[(1S))-1-hydroxyethyl] -N-isopropylbenzenesulfonamide

スルフィンアミンＫ２−１２（４３３ｍｇ、０．６０２ｍｍｏｌ）を６．０２ｍＬのメタノールに入れた溶液に、ＨＣｌ（３．０１ｍＬ、１２．０４ｍｍｏｌ、ジオキサン中４．０Ｍ）を加え、室温で１８時間撹拌した。反応混合物を真空下で濃縮して、ＳＣＸによるクロマトグラフィーで分離して、Ｋ２−１３アミンが得られた。ＬＣ／ＭＳ（Ｍ＋１＝３８７）。

To a solution of sulfinamine K2-12 (433 mg, 0.602 mmol) in 6.02 mL of methanol was added HCl (3.01 mL, 12.04 mmol, 4.0 M in dioxane) and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and separated by chromatography on SCX to give the K2-13 amine. LC / MS (M + 1 = 387).

Procedure K2-14 N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) amino] hexyl}- To a solution of Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide K2-14 (100 mg, 0.236 mmol) in 1.18 mL THF and 1.18 mL saturated NaHCO ₃ solution was added methyl [(1S ) -2-[(2,5-Dioxo-1-pyrrolidinyl) oxy] -1- (diphenylmethyl) -2-oxoethyl] carbamate (141 mg, 0.355 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was diluted with water and ethyl acetate. After separating the organic and aqueous phases, they were collected, dried over Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by reverse phase chromatography to give K2-14. Purification reveals an 8: 1 mixture of diastereomers, which favors the compound. LC / MS (M + 1 = 668). ¹ H NMR CDCl ₃ : δ 7.78 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.99 Hz, 2H), 7.32 to 7.15 (m, 10H), 6 .07 (d, J = 7.19 Hz, 1H), 5.15 (d, J = 9.59 Hz, 2H), 4.96 (q, J = 18.4 Hz, 1H), 4.86 (t, J = 10.8 Hz, 1H), 4.59 (s, 1H), 4.37 (d, J = Hz, 1H), 3.58 (S, 6H), 3.35 (d, J = 24. 8 Hz, 2H), 2.81 (s, 1H), 1.66 (d, J = 6.39 Hz, 3H), 0.959 to 0.924 (m, 4H),
0.695 (t, J = 10.8 Hz, 4H).

Example K3
N-{(1S, 5S) -5-[[(4-acetylphenyl) sulfonyl] (isopropyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide

Ｎ−｛（１Ｓ，５Ｓ）−１−エチル−６−ヒドロキシ−５−［（｛４−［（１Ｓ）−１−ヒドロキシエチル］フェニル｝スルホニル）（イソプロピル）アミノ］ヘキシル｝−Ｎα−（メトキシカルボニル）−β−フェニル−Ｌ−フェニルアラニンアミド（２０ｍｇ、０．０３０ｍｍｏｌ、実施例Ｋ２）を０．２９９ｍＬ アセトンに入れた溶液に、ＭｎＯ_２（１３ｍｇ、０．１５０ｍｍｏｌ）を加えた。結果として生じる混合物を室温で１８時間撹拌した。反応混合物をセライトを通過させて濾過し、逆相クロマトグラフィーで精製して、ケトンＫ３が得られた。ＬＣ／ＭＳ（Ｍ＋１＝６６６）。^１Ｈ ＮＭＲ ＣＤＣｌ_３：δ８．０４（ｄ、Ｊ＝７．５８Ｈｚ、２Ｈ）、７．９４（ｄ、Ｊ＝７．９８Ｈｚ、２Ｈ）、７．３０から７．１６（ｍ，１０Ｈ）、５．５２（ｄ、Ｊ＝９．１８Ｈｚ、１Ｈ）、５．０８（ｄ、Ｊ＝８．７８Ｈｚ、１Ｈ）、４．８１（ｔ、Ｊ＝９．５８Ｈｚ、１Ｈ）、４．５（ｄ、Ｊ＝９．９８Ｈｚ、２Ｈ）、３．８１（ｔ、Ｊ＝Ｈｚ、１Ｈ）３．５８（ｓ、６Ｈ）、３．２７（ｓ、１Ｈ）、２．６４（ｓ，３Ｈ）、１．６４（ｓ，３Ｈ）、１．３１（ｄ、Ｊ＝６．３９Ｈｚ、４Ｈ）、１．２３（ｄ、Ｊ＝７．９８Ｈｚ、６Ｈ）０．７３（ｔ、Ｊ＝７．５８Ｈｚ、４Ｈ）。

N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) amino] hexyl} -Nα- (methoxy To a solution of carbonyl) -β-phenyl-L-phenylalaninamide (20 mg, 0.030 mmol, Example K2) in 0.299 mL acetone was added MnO ₂ (13 mg, 0.150 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite and purified by reverse phase chromatography to give ketone K3. LC / MS (M + 1 = 666). ¹ H NMR CDCl ₃ : δ 8.04 (d, J = 7.58 Hz, 2H), 7.94 (d, J = 7.98 Hz, 2H), 7.30 to 7.16 (m, 10H), 5 .52 (d, J = 9.18 Hz, 1H), 5.08 (d, J = 8.78 Hz, 1H), 4.81 (t, J = 9.58 Hz, 1H), 4.5 (d, J = 9.98 Hz, 2H), 3.81 (t, J = Hz, 1H) 3.58 (s, 6H), 3.27 (s, 1H), 2.64 (s, 3H), 1. 64 (s, 3H), 1.31 (d, J = 6.39 Hz, 4H), 1.23 (d, J = 7.98 Hz, 6H) 0.73 (t, J = 7.58 Hz, 4H) .

The following examples (Table K) show the appropriate building blocks (MeO ₂ C—Ph—SO ₂ Cl or MeCO—Ph—SO ₂ Cl, R ⁵ MgX or CF ₃ TMS, R ¹ OH, HO ₂ C—CHR). ^6- NHR ⁷ or the corresponding active amino acid such as hydroxy succinate), and was made using a procedure similar to that described in the preparation of Examples K1 to K3. In some cases, NHR ⁷ is initially protected as Boc, but the last procedure requires acidic Boc removal.

Example L1
N- (1-{(4S) -4-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -5-hydroxypentyl} cyclopentyl) -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide

手順Ｌ１−１：メチル（２Ｅ）−２−｛［（ベンジルオキシ）カルボニル］アミノ｝−５−（１−ニトロシクロペンチル）ペント−２−エン酸塩

Procedure L1-1: Methyl (2E) -2-{[(benzyloxy) carbonyl] amino} -5- (1-nitrocyclopentyl) pent-2-enoate

４．７３ｍＬ（４４．６ｍｍｏｌ）のニトロシクロペンタンおよび０．１２４ｍＬ（０．８９２ｍｍｏｌ）のトリエチルアミンを含む溶液に、０．５９６ｍＬ（８．９２ｍｍｏｌ）のアクロレインを徐々に加え、その後で反応混合物を１６時間撹拌した。反応混合物を１Ｍ ＨＣｌで急冷し、ＤＣＭで希釈した。層を分離し、有機層を飽和ＮａＨＣＯ_３およびブラインで洗浄した。有機抽出物をＭｇＳＯ_４で乾燥させ、濃縮した。ＤＢＵ（３．４５ｍＬ、２２．８６ｍｍｏｌ）を、（＋／−）−ベンジルオキシカルボニル−α−ホスホノグリシントリメチルエステルをＤＣＭ（４ｍＬ）に入れた溶液に−２０℃で加えた。混合物を５分間撹拌した後、粗製のカルビノールを４ｍＬのＤＣＭに入れた溶液を徐々に加え、追加中に−２０℃の温度を維持した。混合物を、０℃まで温めて５時間撹拌した後、室温で１６時間撹拌した。反応混合物を濃縮した後、ＥｔＯＡｃに再び溶解し、１Ｍ ＨＣｌ、飽和ＮａＨＣＯ_３、水およびブラインで洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮して、油が得られた。物質をこれ以上精製することなく次の反応で使用した。ＬＣＭＳ（Ｍ＋１）＝３７６．９

To a solution containing 4.73 mL (44.6 mmol) nitrocyclopentane and 0.124 mL (0.892 mmol) triethylamine was slowly added 0.596 mL (8.92 mmol) acrolein, after which the reaction mixture was added for 16 hours. Stir. The reaction mixture was quenched with 1M HCl and diluted with DCM. The layers were separated and the organic layer was washed with saturated NaHCO ₃ and brine. The organic extract was dried over MgSO ₄ and concentrated. DBU (3.45 mL, 22.86 mmol) was added to a solution of (+/−)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester in DCM (4 mL) at −20 ° C. After the mixture was stirred for 5 minutes, a solution of crude carbinol in 4 mL DCM was added slowly to maintain a temperature of −20 ° C. during the addition. The mixture was warmed to 0 ° C. and stirred for 5 hours, then at room temperature for 16 hours. The reaction mixture was concentrated then redissolved in EtOAc and washed with 1M HCl, saturated NaHCO ₃ , water and brine. The organic phase was dried over MgSO ₄ and concentrated to give an oil. The material was used in the next reaction without further purification. LCMS (M + 1) = 376.9

Procedure L1-2 Methyl 5- (1-aminocyclopentyl) -N-[(4-nitrophenyl) sulfonyl] norvalinate

化合物Ｌ１−１（２．９５ｇ、７．８４ｍｍｏｌ）を４０ｍＬのＭｅＯＨに溶解し、５５０ｍｇの２０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物を、ＳＴＰで１６時間水素化し、セライトのパッドを通過させて濾過し、蒸発させて、望ましいジアミンが得られた。ジアミンを４０ｍＬのＤＣＥに溶解し、２．８２ｍＬのＴＥＡ（２０．２４ｍｍｏｌ）および１．７９ｇの４−塩化ニトロベンゼンスルホニル（８．１０ｍｍｏｌ）で順に処理した。１６時間撹拌した後、反応混合物をＤＣＭで希釈し、水およびブラインで洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮して、油が得られた。粗製の物質をそれ以上精製することなく手順Ｌ１−３で採用した。ＬＣＭＳ（Ｍ＋１）＝３９９．８

Compound L1-1 (2.95 g, 7.84 mmol) was dissolved in 40 mL MeOH and treated with 550 mg 20% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 16 hours, filtered through a pad of celite and evaporated to give the desired diamine. The diamine was dissolved in 40 mL DCE and treated sequentially with 2.82 mL TEA (20.24 mmol) and 1.79 g 4-nitrobenzenesulfonyl chloride (8.10 mmol). After stirring for 16 hours, the reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over MgSO ₄ and concentrated to give an oil. The crude material was taken in procedure L1-3 without further purification. LCMS (M + 1) = 399.8

Procedure L1-3 Methyl 5- (1-{[N- (methoxycarbonyl) -β-phenyl-L-phenylalanyl] amino} cyclopentyl) -N-[(4-nitrophenyl) sulfonyl] norvalinate

手順Ｌ１−２からのアミン（１ｇ、２．５ｍｍｏｌ）および２，５−ジオキソピロリジン−１−イルＮ−（メトキシカルボニル）−β−フェニル−Ｌ−フェニルアラニナート（９９２ｍｇ、２．５ｍｍｏｌ）を１：１アセトン／ＴＨＦ（２０ｍＬ）に入れた溶液に、１５ｍＬの飽和ＮａＨＣＯ_３を加えた。室温で２時間撹拌した後、反応混合物をＤＣＭで希釈し、Ｈ_２Ｏで洗浄した。水層をＤＣＭで１回抽出し、有機相を混合し、ＭｇＳＯ_４で乾燥させ、濾過し蒸発させた。カラムクロマトグラフィー（勾配：５０％から１００％ＥｔＯＡｃ／ヘキサン）により、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝６８０．９

Procedure Amine from L1-2 (1 g, 2.5 mmol) and 2,5-dioxopyrrolidin-1-yl N- (methoxycarbonyl) -β-phenyl-L-phenylalaninate (992 mg, 2.5 mmol). To a solution in 1: 1 acetone / THF (20 mL) was added 15 mL of saturated NaHCO ₃ . After stirring at room temperature for 2 hours, the reaction mixture was diluted with DCM and washed with H ₂ O. The aqueous layer was extracted once with DCM and the organic phases were combined, dried over MgSO ₄ , filtered and evaporated. Column chromatography (gradient: 50% to 100% EtOAc / hexanes) gave the desired product. LCMS (M + 1) = 680.9

Procedure L1-4 Methyl 5- (1-{[N- (methoxycarbonyl) -β-phenyl-L-phenylalanyl] amino} cyclopentyl) -N- (3-methylbutyl) -N-[(4-nitrophenyl ) Sulfonyl] norvalinate

スルホンアミドＬ１−３（６１０ｍｇ、０．８９６ｍｍｏｌ）を４．５ｍＬのＴＨＦに溶解し、トリフェニルホスフィン（２８２ｍｇ、１．０８ｍｍｏｌ）、イソアミルアルコール（０．１１７ｍＬ、１．０８ｍｍｏｌ）、およびＤＩＡＤ（０．２０９ｍＬ、１．０８ｍｍｏｌ）で順番に処理し、結果として生じる溶液を室温で１６時間撹拌した。反応混合物をＥｔＯＡｃで希釈し、水で洗浄した。有機抽出物をＭｇＳＯ_４で乾燥させ、濃縮し、クロマトグラフィー（勾配：５０％から１００％ＥｔＯＡｃ／ヘキサン）で分離して、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝７５１．０

Sulfonamide L1-3 (610 mg, 0.896 mmol) was dissolved in 4.5 mL THF, triphenylphosphine (282 mg, 1.08 mmol), isoamyl alcohol (0.117 mL, 1.08 mmol), and DIAD (0. 209 mL, 1.08 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic extract was dried over MgSO ₄ , concentrated and separated by chromatography (gradient: 50% to 100% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 751.0

Procedure L1-5 Methyl N-[(4-aminophenyl) sulfonyl] -5- (1-{[N- (methoxycarbonyl) -β-phenyl-L-phenylalanyl] amino} cyclopentyl) -N- (3 -Methylbutyl) norvalinate

化合物Ｌ１−４（５４４ｍｇ、０．７２４ｍｍｏｌ）を３．６ｍＬのＭｅＯＨに溶解し、５１ｍｇの２０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物を、ＳＴＰで１６時間水素化し、セライトのパッドを通過させて濾過し、蒸発させて、望ましいアニリンが得られた。ＬＣＭＳ（Ｍ＋１）＝７２１．１

Compound L1-4 (544 mg, 0.724 mmol) was dissolved in 3.6 mL MeOH and treated with 51 mg 20% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 16 hours, filtered through a pad of celite and evaporated to give the desired aniline. LCMS (M + 1) = 721.1

Procedure L1-6 N- (1-{(4S) -4-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -5-hydroxypentyl} cyclopentyl) -Nα- (methoxycarbonyl) -β - the L1-5 ester of phenyl -L- phenylalanine amide 495 mg (0.687 mmol) to a solution comprising a thing is of EtOH 3 mL, was added 2M LiBH ₄ in 0.34 mL. The reaction mixture was stirred at room temperature for 16 hours, after which 1 mL of water was added and the reaction mixture was stirred at room temperature for 1 hour. The solution was then extracted twice with EtOAc and the organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. The crude material was subjected to reverse phase chromatography and the pure portion was diluted with EtOAc and made basic by addition of saturated NaHCO ₃ . The organic phase was separated, dried and evaporated to give a diastereomeric mixture. Chiral chromatography gave the desired diastereomers.
¹ H NMR (CD3OD): δ 7.48 (d, J = 8.6 Hz, 2H), 7.37 to 7.35 (m, 4H), 7.28 to 7.24 (m, 4H), 7. 19 to 7.14 (m, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.94 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11 .4Hz, 1H), 3.60 to 3.55 (m, 4H), 3.50 to 3.39 (m, 2H), 3.16 to 2.96 (m, 2H), 1.75 to 1 .70 (m, 1H), 1.63 to 1.11 (m, 16H), 0.88 (d, J = 6.14 Hz, 6H). LCMS (M + 1) = 693.3

Example L2
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -β-phenyl-L-phenylalaninamide

手順Ｌ２−１ メチル（２Ｅ）−２−｛［（ベンジルオキシ）カルボニル］アミノ｝−６−メチル−６−ニトロヘプタ−２−エン酸塩

Procedure L2-1 Methyl (2E) -2-{[(benzyloxy) carbonyl] amino} -6-methyl-6-nitrohept-2-enoate

ＤＢＵ（１８．７７ｍＬ、１２５ｍｍｏｌ）を、（＋／−）−ベンジルオキシカルボニル−α−ホスホノグリシントリメチルエステルをＤＣＭ（２００ｍＬ）に入れた溶液に−２０℃で加えた。混合物を５分間撹拌した後、４−メチル−４−ニトロバレルアルデヒドを２６ｍＬのＤＣＭに入れた溶液を徐々に加え、追加中に−２０℃の温度を維持した。混合物を０℃まで温めて５時間撹拌した後、室温で１６時間撹拌した。反応混合物を濃縮し、ＥｔＯＡｃに再び溶かした後、１Ｍ ＨＣｌ、飽和ＮａＨＣＯ_３、水およびブラインで洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮させた。カラムクロマトグラフィー（勾配：２０％から１００％ＥｔＯＡｃ／ヘキサン）により、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝３５１．０

DBU (18.77 mL, 125 mmol) was added to a solution of (+/−)-benzyloxycarbonyl-α-phosphonoglycine trimethyl ester in DCM (200 mL) at −20 ° C. After the mixture was stirred for 5 minutes, a solution of 4-methyl-4-nitrovaleraldehyde in 26 mL DCM was added slowly to maintain a temperature of −20 ° C. during the addition. The mixture was warmed to 0 ° C. and stirred for 5 hours, then at room temperature for 16 hours. The reaction mixture was concentrated and redissolved in EtOAc, then washed with 1M HCl, saturated NaHCO ₃ , water and brine. The organic phase was dried over MgSO ₄ and concentrated. Column chromatography (gradient: 20% to 100% EtOAc / hexanes) gave the desired product. LCMS (M + 1) = 351.0

Procedure L2-2 Methyl (2S) -2-{[(benzyloxy) carbonyl] amino} -6-methyl-6-nitroheptanoate

Ｌ２−１からのオレフィン基質（１２．４４ｇ、３５．５ｍｍｏｌ）および１，２−ビス［（２Ｓ，５Ｓ）−２，５−ジメチルホスホラノ］ベンゼン（シクロオクタジエン）ロジウム（Ｉ）テトラフルオロボラート（３００ｍｇ）を、５０ｍＬ ＭｕｌｔｉＭａｘ^ＴＭ水素付加反応槽（Ｍｅｔｔｌｅｒ Ｔｏｌｅｄｏ）に入れた後、８０ｍＬのＭｅＯＨを入れた。混合物を室温、５０ ｐｓｉで２４時間水素化した。反応混合物を濃縮し、クロマトグラフィー（勾配：４０％から１００％ＥｔＯＡｃ／ヘキサン）で分離して、９６％ｅｅの生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝３５３．１

Olefin substrate from L2-1 (12.44 g, 35.5 mmol) and 1,2-bis [(2S, 5S) -2,5-dimethylphosphorano] benzene (cyclooctadiene) rhodium (I) tetrafluorobo Lat (300 mg) was placed in a 50 mL MultiMax ^™ hydrogenation reactor (Mettler Toledo) followed by 80 mL of MeOH. The mixture was hydrogenated at room temperature and 50 psi for 24 hours. The reaction mixture was concentrated and separated by chromatography (gradient: 40% to 100% EtOAc / hexanes) to give 96% ee product. LCMS (M + 1) = 353.1

Procedure L2-3 Methyl (2S) -6-amino-2-{[(benzyloxy) carbonyl] amino} -6-methylheptanoate

Ｌ２−２からのニトロエステル（１１．６６ｇ、３３．１ｍｍｏｌ）をＭｅＯＨに０℃で溶解し、その後で塩化アセチル（２３．５３ｍＬ、３３１ｍｍｏｌ）を溶液に１０分かけて滴下して加え、温度を０から１２℃に維持した。次に、亜鉛粉（２８．１ｇ、４３０ｍｍｏｌ）を何回かに分けて加え、温度をおよそ０℃に維持した。付加が完了した後、反応混合物を２時間にわたり５５℃に温めた。スラリーを冷まし、濾過し、濃縮し、クロマトグラフィーで分離して、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝３２３．１

The nitro ester from L2-2 (11.66 g, 33.1 mmol) is dissolved in MeOH at 0 ° C., after which acetyl chloride (23.53 mL, 331 mmol) is added dropwise to the solution over 10 minutes, and the temperature is increased. Maintained at 0-12 ° C. Next, zinc powder (28.1 g, 430 mmol) was added in several portions and the temperature was maintained at approximately 0 ° C. After the addition was complete, the reaction mixture was warmed to 55 ° C. over 2 hours. The slurry was cooled, filtered, concentrated and chromatographed to give the desired product. LCMS (M + 1) = 323.1

Procedure L2-4 Methyl (2S) -2-{[(benzyloxy) carbonyl] amino} -6-[(tert-butoxycarbonyl) amino] -6-methylheptanoate

アミンＬ２−３（８ｇ、２４．８ｍｍｏｌ）を１２５ｍＬのＤＣＭに入れた溶液に、５．１９ｍＬ（３７．２ｍｍｏｌ）のＴＥＡを加えた後、Ｂｏｃ_２Ｏ（５．４２ｇ、２４．８ｍｍｏｌ）を加え、室温で１６時間撹拌した。ＤＣＭの容積を減らし、反応混合物をクロマトグラフィー（勾配：２０％から１００％ＥｔＯＡｃ／ヘキサン）で分離して、保護アミンが得られた。ＬＣＭＳ（Ｍ＋１）＝４２３．２

To a solution of amine L2-3 (8 g, 24.8 mmol) in 125 mL DCM was added 5.19 mL (37.2 mmol) TEA followed by Boc ₂ O (5.42 g, 24.8 mmol). And stirred at room temperature for 16 hours. The volume of DCM was reduced and the reaction mixture was separated by chromatography (gradient: 20% to 100% EtOAc / hexanes) to give the protected amine. LCMS (M + 1) = 423.2

Procedure L2-5 Methyl (2S) -2-amino-6-[(tert-butoxycarbonyl) amino] -6-methylheptanoate

化合物Ｌ２−４（５．４８ｇ、１２．９７ｍｍｏｌ）を６５ｍＬのＭｅＯＨに溶解し、９１１ｍｇの２０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物を、ＳＴＰで１６時間水素化し、セライトのパッドを通過させて濾過し、蒸発させ、望ましいアミンが得られた。ＬＣＭＳ（Ｍ＋１）＝２８９．１

Compound L2-4 (5.48 g, 12.97 mmol) was dissolved in 65 mL MeOH and treated with 911 mg 20% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 16 hours, filtered through a pad of celite and evaporated to give the desired amine. LCMS (M + 1) = 289.1

Procedure L2-6 Methyl (2S) -6-[(tert-butoxycarbonyl) amino] -6-methyl-2-{[(4-nitrophenyl) sulfonyl] amino} heptanoate

アミンＬ２−５（３．４３ｇ、１１．８９ｍｍｏｌ）を６０ｍＬのＤＣＭに溶解し、２．４９ｍＬのＴＥＡ（１７．８４ｍｍｏｌ）および２．６４ｇの４−塩化ニトロベンゼンスルホニル（１１．８９ｍｍｏｌ）で順に処理した。１６時間撹拌した後、反応混合物をＤＣＭで希釈し、水およびブラインで洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濃縮させた。カラムクロマトグラフィー（勾配：２０％から１００％ＥｔＯＡｃ／ヘキサン）により、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝４７５．１

Amine L2-5 (3.43 g, 11.89 mmol) was dissolved in 60 mL DCM and treated sequentially with 2.49 mL TEA (17.84 mmol) and 2.64 g 4-nitrobenzenesulfonyl chloride (11.89 mmol). . After stirring for 16 hours, the reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over MgSO ₄ and concentrated. Column chromatography (gradient: 20% to 100% EtOAc / hexanes) gave the desired product. LCMS (M + 1) = 475.1

Procedure L2-7 Methyl (2S) -6-[(tert-butoxycarbonyl) amino] -2- {isopropyl [(4-nitrophenyl) sulfonyl] amino} -6-methylheptanoate

スルホンアミドＬ２−６（３．４ｇ、７．１８ｍｍｏｌ）を３６ｍＬのＴＨＦに溶解し、トリフェニルホスフィン（２．２６ｇ、８．６２ｍｍｏｌ）、２−プロパノール（０．６６ｍＬ、８．６２ｍｍｏｌ）、およびＤＩＡＤ（１．６８ｍＬ、８．６２ｍｍｏｌ）で順番に処理し、結果として生じる溶液を室温で１６時間撹拌した。反応混合物をＥｔＯＡｃで希釈し、水で洗浄した。有機相をＭｇＳＯ_４上で乾燥させ、濾過し、濃縮し、クロマトグラフィー（勾配：１０％から８０％ＥｔＯＡｃ／ヘキサン）で分離して、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝５１６．２

Sulfonamide L2-6 (3.4 g, 7.18 mmol) was dissolved in 36 mL THF, triphenylphosphine (2.26 g, 8.62 mmol), 2-propanol (0.66 mL, 8.62 mmol), and DIAD (1.68 mL, 8.62 mmol) in order and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried over MgSO ₄ , filtered, concentrated, and chromatographed (gradient: 10% to 80% EtOAc / hexanes) to give the desired product. LCMS (M + 1) = 516.2

Procedure L2-8 Methyl (2S) -2-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-[(tert-butoxycarbonyl) amino] -6-methylheptanoate

化合物Ｌ２−７（２．３１ｇ、４．４８ｍｍｏｌ）を２２ｍＬのＭｅＯＨに溶解し、３１５ｍｇの２０％Ｐｄ（ＯＨ）_２で処理した。結果として生じる混合物を、ＳＴＰで１６時間水素化し、セライトのパッドを通過させて濾過し、蒸発させて、望ましいアニリンが得られた。ＬＣＭＳ（Ｍ＋１）＝４８６．２

Compound L2-7 (2.31 g, 4.48 mmol) was dissolved in 22 mL of MeOH and treated with 315 mg of 20% Pd (OH) ₂ . The resulting mixture was hydrogenated with STP for 16 hours, filtered through a pad of celite and evaporated to give the desired aniline. LCMS (M + 1) = 486.2

Procedure L2-9 tert-butyl {(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} carbamate

２．１６ｇ（４．４５ｍｍｏｌ）のＬ２−８ エステルを２２ｍＬのＥｔＯＨに入れたものを含む溶液に、８．９１ｍＬの２Ｍ ＬｉＢＨ_４を加えた。反応混合物を２時間撹拌した後、５ｍＬの水を加え、混合物を３０分間撹拌した。溶液をＥｔＯＡｃで２回抽出し、有機相を水およびブラインで洗浄し、ＭｇＳＯ_４で乾燥させて濃縮させた。カラムクロマトグラフィー（勾配：５０％から１００％ＥｔＯＡｃ／ヘキサン）により、望ましいアルコールが得られた。ＬＣＭＳ（Ｍ＋１）＝４５８．３

The L2-8 ester 2.16 g (4.45 mmol) to a solution comprising a thing is of EtOH 22 mL, was added 2M LiBH ₄ in 8.91ML. After the reaction mixture was stirred for 2 hours, 5 mL of water was added and the mixture was stirred for 30 minutes. The solution was extracted twice with EtOAc and the organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. Column chromatography (gradient: 50% to 100% EtOAc / hexanes) gave the desired alcohol. LCMS (M + 1) = 458.3

Procedure L2-10 4-amino-N-[(1S) -5-amino-1- (hydroxymethyl) -5-methylhexyl] -N-isopropylbenzenesulfonamide

化合物Ｌ２−９（１．６２ｇ、３．５４ｍｍｏｌ）を２０ｍＬのＭｅＯＨに０℃で溶解した後、ＨＣｌガス流を溶液に２分間通過させた。反応混合物をさらに２時間攪拌した後、溶剤を除去し、望ましいアミノアルコール塩酸塩（ＨＣＩ）が得られたが、これをそれ以上精製することなく手順Ｌ２−１１で使用した。ＬＣＭＳ（Ｍ＋１）＝３５８．１

Compound L2-9 (1.62 g, 3.54 mmol) was dissolved in 20 mL of MeOH at 0 ° C. and then a stream of HCl gas was passed through the solution for 2 minutes. After the reaction mixture was stirred for an additional 2 hours, the solvent was removed to give the desired amino alcohol hydrochloride (HCI), which was used in Procedure L2-11 without further purification. LCMS (M + 1) = 358.1

Procedure L2-11N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (tert-butoxycarbonyl) -β -Phenyl-L-phenylalaninamide

手順Ｌ２−１０からのアミン塩酸塩（ＨＣＩ）（５０ｍｇ、０．１２７ｍｍｏｌ）およびＮ−Ｂｏｃ−（Ｓ）−ジフェニルアラニン（４３ｍｇ、０．１２７ｍｍｏｌ）を１ｍＬのＤＭＦに入れた溶液に、ジイソプロピルエチルアミン（０．０７ｍＬ、０．３８１ｍｍｏｌ）およびＢＯＰ試薬（５６ｍｇ、０．１２７ｍｍｏｌ）を加えた。２時間後、反応混合物を逆相クロマトグラフィーにかけた。純粋な部分をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３を加えて、塩基性にした。有機相を分離し乾燥させ、蒸発させて、望ましい生成物が得られた。ＬＣＭＳ（Ｍ＋１）＝６８１．３

To a solution of amine hydrochloride (HCI) (50 mg, 0.127 mmol) and N-Boc- (S) -diphenylalanine (43 mg, 0.127 mmol) from Procedure L2-10 in 1 mL of DMF was added diisopropylethylamine ( 0.07 mL, 0.381 mmol) and BOP reagent (56 mg, 0.127 mmol) were added. After 2 hours, the reaction mixture was subjected to reverse phase chromatography. The pure portion was diluted with EtOAc and made basic by addition of saturated NaHCO ₃ . The organic phase was separated, dried and evaporated to give the desired product. LCMS (M + 1) = 681.3

Procedure L2-12 N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -β-phenyl-L-phenylalaninamide compound L2-11 (50 mg, 0.073 mmol) was dissolved in 1.5 mL of MeOH at 0 ° C., after which a stream of HCl gas was passed through the solution for 2 minutes. After stirring the reaction mixture for an additional 2 hours, the solvent was removed to give the desired product, hydrochloride, as a white solid. ¹ H NMR (CD3OD): δ 7.81 (d, J = 8.5 Hz, 2H), 7.50 to 7.48 (m, 2H), 7.41 to 7.37 (m, 4H), 7. 34 to 7.24 (m, 4H), 7.13 (d, J = 8.5 Hz, 2H), 4.68 (d, J = 11.3 Hz, 1H), 4.28 (d, J = 11 .4Hz, 1H), 3.76 to 3.70 (m, 1H), 3.60 to 3.59 (m, 2H), 3.43 (m, 1H), 1.56 (m, 2H), 1.40 to 1.04 (m, 10H), 1.01 (s, 3H), 0.92 (s, 3H). LCMS (M + 1) = 581.3

The following examples (Table L) show examples L1 to L2 using the appropriate building blocks (corresponding active amino acids such as R ¹ OH, HO ₂ C—CHR ⁶ —NHR ⁷ or hydroxysuccinate). Prepared using a procedure similar to that described in the preparation of In some cases, NHR ⁷ was initially protected as Boc, but the last procedure required acidic Boc removal.

Example M1
N- [5-[[(4-Aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (hydroxymethyl) hexyl] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalanine Amide

手順Ｍ１−１：１，７−ジメトキシ−１，７−ジオキソヘプタン−２，６−二塩化ジアミニウム

Procedure M1-1: 1,7-dimethoxy-1,7-dioxoheptane-2,6-diaminium dichloride

２５．０ｇ（１３１ｍｍｏｌ）の２，６−ジアミノヘプタン二酸を１００ｍＬのメタノールに入れたものを含む０℃の溶液に、５００ｍＬ １．２５Ｍ ＨＣｌをＭｅＯＨに入れたものを加えた。溶液を室温まで温め、１６時間撹拌した。反応混合物を０℃まで冷まし、ＨＣｌガスを通して１０分間泡立てた。結果として生じる混合物を室温まで温め、１６時間撹拌した後、濃縮して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝２１９。

To a 0 ° C. solution containing 25.0 g (131 mmol) of 2,6-diaminoheptanedioic acid in 100 mL of methanol was added 500 mL of 1.25 M HCl in MeOH. The solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 ° C. and bubbled through HCl gas for 10 minutes. The resulting mixture was warmed to room temperature, stirred for 16 hours, and then concentrated to give the desired product. LCMS [M + H] ⁺ = 219.

Procedure M1-2: Dimethyl 2-amino-6-{[(benzyloxy) carbonyl] amino} heptanedioate

手順Ｍ１−１からの３０．６ｇ（１０５ｍｍｏｌ）のジエステルを２００ｍＬのジクロロメタンに入れたものを含む０℃溶液に、３０．８ｍＬ（２２１ｍｍｏｌ）トリエチルアミンを加えた後、１．５ｍＬ（１０．５１ｍｍｏｌ）ベンジルクロロギ酸塩を滴下して加えた。溶液を室温まで温め、１６時間撹拌した後、濃縮した。残留物をエーテルと１Ｎ ＨＣｌに分離した。水層を固体炭酸水素ナトリウムを加えて塩基性にした後、エーテル（４ｘ）で抽出した。有機抽出物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ_、濃縮し、クロマトグラフィー（０％から１０％ＭｅＯＨ／ＥｔＯＡｃ）で分離して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝３５３。

Procedure To a 0 ° C. solution containing 30.6 g (105 mmol) of the diester from M1-1 in 200 mL of dichloromethane was added 30.8 mL (221 mmol) of triethylamine followed by 1.5 mL (10.51 mmol) of benzyl. Chloroformate was added dropwise. The solution was warmed to room temperature, stirred for 16 hours and then concentrated. The residue was separated between ether and 1N HCl. The aqueous layer was basified with solid sodium hydrogen carbonate and extracted with ether (4x). The organic extract was washed with brine, dried over Na ₂ SO _{4 ,} concentrated and separated by chromatography (0-10% MeOH / EtOAc) to give the desired product. LCMS [M + H] ⁺ = 353.

Procedure M1-3: Dimethyl 2-{[(benzyloxy) carbonyl] amino} -6-{[(4-nitrophenyl) sulfonyl] amino} heptanedioate

手順Ｍ１−２からの１．１５ｇ（３．２６ｍｍｏｌ）のアミンを１００ｍＬ ＤＣＭに入れたものを含む溶液に、０．７２３ｇ（３．２６ｍｍｏｌ）のｐ−塩化ニトロベンゼンスルホニルを加えた後、０．４６ｍＬ（３．２６ｍｍｏｌ）のトリエチルアミンを加えた。結果として生じる混合物を室温で１６時間攪拌させた。溶液を１ Ｎ ＨＣｌで洗浄し、飽和ＮａＨＣＯ_３、水、およびブラインで洗浄した。有機相をＮａ_２ＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィーで分離して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝５３８。

To a solution containing 1.15 g (3.26 mmol) of amine from procedure M1-2 in 100 mL DCM was added 0.723 g (3.26 mmol) of p-nitrobenzenesulfonyl chloride followed by 0.46 mL. (3.26 mmol) of triethylamine was added. The resulting mixture was allowed to stir at room temperature for 16 hours. The solution was washed with 1 N HCl, washed with saturated NaHCO ₃ , water, and brine. The organic phase was dried over Na ₂ SO ₄ , concentrated and chromatographed to give the desired product. LCMS [M + H] ⁺ = 538.

Procedure M1-4: 2-{[(Benzyloxy) carbonyl] amino} -6-{(3-methylbutyl) [(4-nitrophenyl) sulfonyl] amino} heptanedioic acid dimethyl

手順Ｍ１−３からの１．５２ｇ（２．８３ｍｍｏｌ）の生成物を８ｍＬ ＴＨＦに入れた溶液に、０．８１６ｇ（３．１１ｍｍｏｌ）トリフェニルホスフィンを加えた後、０．４０１ｍＬ（３．６８ｍｍｏｌ）イソアミルアルコールを加えた。溶液を脱気し、０．６０５ｍＬ（３．１１ｍｍｏｌ）ＤＩＡＤを加えた。溶液を室温で１６時間撹拌し、濃縮し、クロマトグラフィーで分離して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝６０８。

To a solution of 1.52 g (2.83 mmol) of product from Procedure M1-3 in 8 mL THF was added 0.816 g (3.11 mmol) triphenylphosphine followed by 0.401 mL (3.68 mmol). Isoamyl alcohol was added. The solution was degassed and 0.605 mL (3.11 mmol) DIAD was added. The solution was stirred at room temperature for 16 hours, concentrated and chromatographed to give the desired product. LCMS [M + H] ⁺ = 608.

Procedure M1-5: Dimethyl 2-amino-6-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] heptanedioate

手順Ｍ１−４からの２．０ｇ（３．２９ｍｍｏｌ）の生成物を含む脱気した溶液を、６ｍＬのＭｅＯＨに溶解したものを、２．３１ｇの１０％Ｐｄ（ＯＨ）_２で処理し、ＳＴＰで２時間にわたり水素化した。反応混合物をセライトを通過させて濾過し、濃縮して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋Ｈ］^＋＝４４４。

Procedure Degassed solution containing 2.0 g (3.29 mmol) of product from M1-4 dissolved in 6 mL of MeOH was treated with 2.31 g of 10% Pd (OH) ₂ to give STP. And hydrogenated for 2 hours. The reaction mixture was filtered through celite and concentrated to give the desired product. LCMS [M + H] ⁺ = 444.

Procedure M1-6: Dimethyl 2-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-{[N- (methoxycarbonyl) -β-phenyl-L-phenylalanyl] amino} heptane Dimethyl diacid

手順Ｍ１−５の１．６６ｇ（３．７４ｍｍｏｌ）の生成物を８ｍＬの１：１ ＴＨＦ：アセトンに入れた溶液に、１．４８ｇ（３．７４ｍｍｏｌ）の２，５−ジオキソピロリジン−１−イルＮ−（メトキシカルボニル）−β−フェニル−Ｌ−フェニルアラニナートを加えた後、４ｍＬの飽和ＮａＨＣＯ_３を加えた。懸濁液を室温で１６時間撹拌した後、濃縮した。残留物をＤＣＭに溶解し、水およびブラインで洗浄した。有機相をＮａ_２ＳＯ_４上で乾燥させ、濃縮し、クロマトグラフィーで分離して、望ましい生成物が得られた。ＬＣＭＳ［Ｍ＋１］^＋＝７２５。

To a solution of 1.66 g (3.74 mmol) of procedure M1-5 in 8 mL of 1: 1 THF: acetone, 1.48 g (3.74 mmol) of 2,5-dioxopyrrolidine-1- After adding yl N- (methoxycarbonyl) -β-phenyl-L-phenylalaninate, 4 mL of saturated NaHCO ₃ was added. The suspension was stirred at room temperature for 16 hours and then concentrated. The residue was dissolved in DCM and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , concentrated and chromatographed to give the desired product. LCMS [M + 1] ⁺ = 725.

Procedure M1-7: N- [5-[[(4-Aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (hydroxymethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide

手順Ｍ１−６からの１．４４ｇ（１．９８７ｍｍｏｌ）の生成物を６ｍＬ ＴＨＦに入れた溶液に、３．９７ｍＬの２Ｍ ＬｉＢＨ_４を加えた。反応混合物を３０分間撹拌させてから、０．５ｍＬのＭｅＯＨを加えた。さらに１時間攪拌した後、反応混合物をＭｅＯＨで急冷し、濃縮した。残留物をＤＣＭに溶解し、水およびブラインで洗浄した。有機相をＮａ_２ＳＯ_４上で乾燥させ、濃縮し、逆相クロマトグラフィーにかけた。純粋な部分をＥｔＯＡｃで希釈し、飽和ＮａＨＣＯ_３を加えて塩基性にした。有機相を分離し、Ｎａ_２ＳＯ_４で乾燥させ、蒸発させて、望ましい生成物が４種のジアステレオマーの混合物として得られた。ジアステレオマーの混合物を、ｃｈｉｒａｌｐａｋ ＡＤ−Ｈ（アミローストリス（３，５−ジメチルフェニルカルバミン酸塩）カラム、内径３ｃｍ×２５ｃｍ、５μｍ、ＣＯ_２中４０％ＩＰＡ）でのキラルクロマトグラフィーにかけ、可能性のある４つのジアステレオマーの２対が得られた。それぞれの対を濃縮して、異なる方法（Ｋｒｏｍａｓｉｌ^Ｒキラル（Ａｋｚｏ Ｎｏｂｅｌ）ＴＢＢ（Ｏ，Ｏ’−ビス（４−ｔｅｒｔ−ブチルベンゾイル）−Ｎ，Ｎ’−ジアリル−Ｌ−酒石ジアミド）、内径３ｃｍ×２５ｃｍ、５μｍ、ＣＯ_２中２５％ＩＰＡ）での第２のキラルクロマトグラフィーにかけた。それぞれの対から、１つは活性の異性体、もう１つは不活性の異性体にそれぞれ単離した。活性のジアステレオ異性体は以下のとおりである。

To a solution of 1.44 g (1.987 mmol) of product from Procedure M1-6 in 6 mL THF was added 3.97 mL of 2M LiBH ₄ . The reaction mixture was allowed to stir for 30 minutes before 0.5 mL of MeOH was added. After stirring for an additional hour, the reaction mixture was quenched with MeOH and concentrated. The residue was dissolved in DCM and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , concentrated and subjected to reverse phase chromatography. The pure portion was diluted with EtOAc and made basic by addition of saturated NaHCO ₃ . The organic phase was separated, dried over Na ₂ SO ₄ and evaporated to give the desired product as a mixture of 4 diastereomers. The mixture of diastereomers was subjected to chiral chromatography on a chiralpak AD-H (amylose tris (3,5-dimethylphenylcarbamate) column, ID 3 cm × 25 cm, 5 μm, 40% IPA in CO ₂ ), possibility Two pairs of four diastereomers were obtained. Concentration of the respective pairs, different methods (Kromasil ^R chiral (Akzo Nobel) TBB (O, O'- bis (4-tert-butyl-benzoyl) -N, N'-diallyl -L- tartar diamide), inner diameter 3 cm x 25 cm, 5 μm, 25% IPA in CO ₂ ). From each pair, one was isolated as the active isomer and the other as the inactive isomer. The active diastereoisomers are as follows:

Example M1-7A: N-[(1R or 1S, 5R or 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (hydroxymethyl) hexyl ] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide (second eluting isomer)
¹ H NMR (CDCl ₃ ): δ 7.62 to 7.61 (m, 2H), 7.33 to 7.23 (m, 10H), 6.75 to 6.60 (m, 2H), 5.84 (Br s, 1H), 5.25 to 5.20 (m, 1H), 4.86 to 4.82 (t, J = 9 Hz, 1H), 4.40 to 4.37 (m, 1H), 3.65 to 3.50 (m, 7H), 3.20 to 3.04 (m, 4H), 2.35 (br s, 4H), 1.56 to 1.21 (m, 8H), 1 .00 to 0.89 (m, 7H). LCMS [M + H] ⁺ = 669.

Example M1-7B: N-[(1R or 1S, 5R or 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (hydroxymethyl) hexyl ] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide (fourth eluting isomer)
¹ H NMR (CDCl ₃ ): δ 7.62 to 7.59 (m., 2H), 7.33 to 7.26 (m, 10H), 6.72 to 6.70 (m, 2H), 5. 69 (br s, 1H), 5.13 to 5.11 (m, 1H), 4.77 to 4.3 (t, J = 9 Hz, 1H), 4.44 to 4.42 (d, J = 11 Hz, 1H), 4.30 (br s, 2H), 3.61 to 3.42 (m, 8H), 3.30 to 3.19 (m, 2H), 3.16 to 3.01 (m) 1H), 2.62 (br s, 1H), 2.30 (br s, 1H), 1.57 (br s, 3H), 1.26 to 0.90 (m, 10H), 0.57 (Br s, 2H). LCMS [M + H] ⁺ = 669.

Example 1 of test method
Test Method for Inhibition of Microbial-Expressed HIV Protease Inhibition studies on the reaction of protease (expressed in E. coli) with peptide substrate [Val-Ser-Gln-Asn- (betanaphthyl) Ala-Pro-Ile-Val]. Inhibitors are first preincubated with the enzyme in test buffer (50 mM sodium acetate, pH 5.5, 100 mM NaCl, and 0.1% BSA) for 30 minutes at room temperature. The substrate is added to 440 micromoles in a total volume of 80 microliters containing 5 pmoles of HIV-1 protease and the reaction is incubated at 30 ° C. for 1 hour. 120 microliters of 10% phosphoric acid is added to quench the reaction and product formation is identified after separation of product and substrate on a Vydac C18 column connected to an Alliance high performance liquid chromatography system (Waters Corporation) To do. The degree of inhibition of the reaction is judged from the peak area of the product. Product HPLC, proven independently quantified standards and confirmation of product composition. Representative compounds of the present invention show inhibition of HIV-1 protease in this test method. For example, as the IC ₅₀ values show in Table 1 below, the compounds described in the above examples show inhibition against the wild type HIV-1 protease enzyme.

Example 2 of test method
Test Method for Inhibition of HIV Replication The test method for the inhibition of acute HIV infection of T lymphoid cells is according to “Vacca, JP et al., Proc. Natl. Acad. Sci. USA 1994, 91 : 4096”. Carried out. Representative compounds of the invention have shown inhibition of HIV replication in this test method (also referred to herein as “spread assay”). For example, as indicated by its IC ₉₅ value in Table 1 below, the compounds described in the above examples were tested in this test method and were found to exhibit inhibition of HIV-1 replication.

Example 3 of test method
Cytotoxicity Cytotoxicity was determined by microscopic examination of the cells in each well in the spread assay, where the analysts trained here added to each culture as compared to the control culture. , Observed for morphological changes such as pH imbalance, cell abnormalities, cell division arrest, cell degeneration, or crystallization (ie, the compound is not soluble or crystals are formed in the wells). . The toxicity value assigned to a given compound is the lowest concentration of compound at which the above changes were observed. Representative compounds of the present invention do not exhibit cytotoxicity. For example, all the exemplified compounds were tested in this test method, but none showed cytotoxicity.

In certain compounds of the invention, including certain exemplified compounds (eg, certain compounds encompassed by Formula III), the epsilon position (ie, one or both of R ⁵ and R ^5A in Compound I is not H). ) Are structurally similar compounds that are unbranched at the β, γ, δ, and epsilon (ε) positions (ie, R ³ = R ⁴ = R ⁵ = R ^5A = H) Have shown higher potency in the above test methods and / or better PK profiles in animal models. Of particular interest in this regard are certain compounds included in Formula V.

  While the foregoing specification teaches the principles of the invention and examples have been provided for purposes of illustration, the invention may be practiced in the form of any conventional variations, adaptations that fall within the scope of the following claims. And / or changes. All documents, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims (21)

Compound of formula I

Or a pharmaceutically acceptable salt thereof, wherein
R ¹ _{is C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 C 1-6} alkyl substituted with cycloalkyl or _{C 3-6} cycloalkyl,
R ² is CH (R ^J ) —Z, and Z is OH, NH ₂ , or OR ^P ;
R ^J is, _H, a _{C 1-6 alkyl, C 1-6} fluoroalkyl or _{C 1-6} alkyl substituted with _{C 3-5} cycloalkyl,
R ^P is P (O) (OH) ₂ , P (O) (OM) ₂ , or C (O) R ^Q ;
M is an alkali metal or alkaline earth metal;
^RQ is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C (O) —C _1-6 alkylene-N (H) —C _1-6 alkyl,
(9) C (O) —C _1-6 alkylene-N (—C _1-6 alkyl) ₂ ,
(10) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(11) C _1-6 alkyl substituted with C (O) OH;
(12) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(13) N (H) —C _1-6 alkyl,
(14) N (—C _1-6 alkyl) ₂ ,
(15) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(16) AryA,
(17) C _1-6 alkyl substituted with AryA,
(18) O—C _1-6 alkyl substituted with AryA,
(19) HetA,
(20) C _1-6 alkyl substituted with HetA,
(21) O—C _1-6 alkyl substituted with HetA,
(22) HetB, or (23) O-HetB
And
R ³ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl,
R ⁴ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-6 cycloalkyl,
R ⁵ is, _{H, C 1-6 alkyl, C 1-6} fluoroalkyl alkyl, _C substituted with OH _{1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6} cycloalkyl or C, C _1-6 alkyl substituted with _3-6 cycloalkyl,
R ^5A is H or C _1-6 alkyl;
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-6 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) When either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H; and (C) When R ³ and R ⁴ are not H, R ⁵ and R ^5A are both H;
Each of ^{X A} is, independently:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 haloalkyl,
(4) OH
(5) O—C _1-6 alkyl,
(6) O—C _1-6 haloalkyl,
(7) O—C _3-6 cycloalkyl,
(8) SH,
(9) S—C _1-6 alkyl,
(10) S—C _1-6 haloalkyl,
(11) S—C _3-6 cycloalkyl,
(12) Halo,
(13) CN,
(14) NO ₂ ,
(15) NH ₂ ,
(16) N (H) -C _1-6 alkyl,
(17) N (—C _1-6 alkyl) ₂ ,
(18) N (H) C (O) —C _1-6 alkyl,
(19) N (H) CH (O),
(20) CH (O),
(21) C (O) —C _1-6 alkyl,
(22) C (O) OH,
(23) C (O) O—C _1-6 alkyl,
(24) SO ₂ H,
₍₂₅₎ SO _{2 -C 1-6} alkyl or, (26)
(A) C _3-6 cycloalkyl,
(B) C _1-6 haloalkyl,
(C) OH,
(D) O—C _1-6 alkyl,
(E) O—C _1-6 haloalkyl,
(F) O—C _3-6 cycloalkyl,
(G) SH,
(H) S—C _1-6 alkyl,
(I) S—C _1-6 haloalkyl,
(J) S—C _3-6 cycloalkyl,
(K) Halo,
(L) CN,
(M) NO ₂ ,
(N) NH ₂ ,
(O) N (H) -C _1-6 alkyl,
(P) N (—C _1-6 alkyl) ₂ ,
(Q) N (H) C (O) —C _1-6 alkyl,
(R) N (H) CH (O),
(S) CH (O),
(T) C (O) —C _1-6 alkyl,
(U) C (O) OH,
(V) C (O) O—C _1-6 alkyl,
(W) _SO 2 H, or _(x) SO _{2 -C 1-6} alkyl,
C _1-6 alkyl substituted with
Alternatively, more than one X ^A substituents are present in the phenyl ring, and when it two of X ^A is attached to the carbon atom adjacent to the phenyl ring, the two X ^A, and they are attached Together with the carbon atom present may form a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains 1 to 2 heteroatoms,
K is an integer equal to 0, 1, 2, or 3;
R ⁶ is:

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
R ^6A is H or C _1-6 alkyl;
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached are optionally substituted with C _3-6 cycloalkyl (wherein phenyl is optionally substituted with 1 to 3 X ^B. )
Each X ^B and each X ^C is
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 haloalkyl,
(4) OH,
(5) O—C _1-6 alkyl,
(6) O—C _1-6 haloalkyl,
(7) O—C _3-6 cycloalkyl,
(8) SH,
(9) S—C _1-6 alkyl,
(10) S—C _1-6 haloalkyl,
(11) S—C _3-6 cycloalkyl,
(12) Halo,
(13) CN,
(14) NO ₂ ,
(15) NH ₂ ,
(16) N (H) -C _1-6 alkyl,
(17) N (—C _1-6 alkyl) ₂ ,
(18) N (H) C (O) —C _1-6 alkyl,
(19) N (H) CH (O),
(20) CH (O),
(21) C (O) —C _1-6 alkyl,
(22) C (O) OH,
(23) C (O) O—C _1-6 alkyl,
(24) SO ₂ H,
₍₂₅₎ SO _{2 -C 1-6} alkyl, and (26)
(A) C _1-6 haloalkyl,
(B) OH
(C) O—C _1-6 alkyl,
(D) O—C _1-6 haloalkyl,
(E) O—C _3-6 cycloalkyl,
(F) SH,
(G) S—C _1-6 alkyl,
(H) Halo,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) —C _1-6 alkyl,
(M) N (—C _1-6 alkyl) ₂ ,
(N) C (O) —C _1-6 alkyl,
(O) C (O) OH,
(P) C (O) O—C _1-6 alkyl, or (q) SO ₂ —C _1-6 alkyl,
Independently selected from the group consisting of C _1-6 alkyl substituted with
T is O, S, S (O), or SO ₂ ;
m is an integer equal to 0, 1, 2, or 3;
n is an integer equal to 0, 1, 2, or 3;
R ⁷ is, _H, a _{C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6} alkyl substituted with _{C 3-6} cycloalkyl or C (O) -R ^K,,
R ⁸ is H or C _1-6 alkyl;
^RK is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(9) C _1-6 alkyl substituted with C (O) OH,
(10) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(11) N (H) -C _1-6 alkyl,
(12) N (—C _1-6 alkyl) ₂ ,
(13) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(14) AryA,
(15) C _1-6 alkyl substituted with AryA,
(16) O—C _1-6 alkyl substituted with AryA,
(17) HetA,
(18) C _1-6 alkyl substituted with HetA,
(19) O—C _1-6 alkyl substituted with HetA,
(20) HetB,
(21) O-HetB, or (22) O-C _1-6 alkyl substituted with HetB,
Each AryA is an independently phenyl or naphthyl aryl, wherein the phenyl or naphthyl is substituted from one to any of four Y ^B, each Y ^B is a independently X ^B Have the same definition,
Each HetA is independently (i) a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from N, O and S, or (ii) quinolinyl, isoquinolinyl And heteroaryl, a heterobicyclic ring selected from quinoxalinyl, wherein the heteroaromatic ring (i) or bicyclic ring (ii) is optionally selected from 1 to 4 Y ^C Where each Y ^C independently has the same definition as X ^B
Each HetB is independently a 4- to 7-membered saturated or unsaturated, non-aromatic heterocycle, from 1 to 4 independently selected from at least one carbon atom and N, O and S Having heteroatoms, where each S is optionally oxidized to S (O) or S (O) _2, and where a saturated or unsaturated heterocycle is independently halogen, CN , C _1-6 alkyl, OH, oxo, O—C _1-6 alkyl, C _1-6 haloalkyl, O—C _1-6 haloalkyl, C (O) NH ₂ , C (O) N (H) —C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C (O) H, C (O) —C _1-6 alkyl, CO ₂ H, CO ₂ —C _1-6 alkyl, SO ₂ H or _SO 2 _{-C 1-6} 1 from 4 substituents are alkyl, Is optionally substituted. ).
This corresponds to the original PV claim 1. 2. A compound according to claim 1 which is a compound of formula IA.

Or a pharmaceutically acceptable salt thereof (wherein
R ¹ _{is C 1-6} alkyl substituted with _{C 1-6} alkyl or _{C 3-6} cycloalkyl,
R ³ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-5 cycloalkyl,
R ⁴ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-5 cycloalkyl,
R ⁵ is H, C _1-6 alkyl, C _1-6 fluoroalkyl, or C _1-6 alkyl substituted with C _3-5 cycloalkyl,
However:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is C _1-6 alkyl, C _1-6 fluoroalkyl, or C _3- C _1-6 alkyl substituted with ₅ cycloalkyl, and (B) at least one of R ³ , R ⁴ , and R ⁵ is H, and each X ^A is independently As defined in
Alternatively, when two or more X ^A substituents are present on the phenyl ring and the two X ^A are bonded to adjacent carbon atoms of the phenyl ring, the two X ^A together are —OCH ₂ O— or -OCH ₂ CH ₂ O- to form,
R ⁶ is:

Where the asterisk (*) indicates the point of attachment to the other part of the compound, and ^RK is:
(1) C _1-6 alkyl,
(2) C _3-6 cycloalkyl,
(3) C _1-6 alkyl substituted with C _3-6 cycloalkyl,
(4) O—C _1-6 alkyl,
(5) O—C _1-6 alkyl substituted with O—C _1-6 alkyl,
(6) O—C _1-6 fluoroalkyl,
(7) C (O) O—C _1-6 alkyl,
(8) C _1-6 alkyl substituted with C (O) O—C _1-6 alkyl,
(9) C _1-6 alkyl substituted with C (O) OH,
(10) C _1-6 alkyl substituted with C (O) —C _1-6 alkyl,
(11) N (H) -C _1-6 alkyl,
(12) N (—C _1-6 alkyl) ₂ ,
(13) C _1-6 alkyl substituted with NH ₂ , N (H) —C _1-6 alkyl, or N (—C _1-6 alkyl) ₂ ,
(14) AryA,
(15) C _1-6 alkyl substituted with AryA,
(16) O—C _1-6 alkyl substituted with AryA,
(17) HetA,
(18) C _1-6 alkyl substituted with HetA,
(19) O—C _1-6 alkyl substituted with HetA,
(20) HetB, or (21) O-HetB
It is. ). R ¹ is C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-5 cycloalkyl, or CH ₂ -C _3-5 cycloalkyl,
R ² is CH ₂ —Z, CH (CH ₃ ) —Z, CH (CF ₃ ) —Z, where Z is OH, NH ₂ , or OR ^P , and ^RP is P (O ) (OH) ₂ , P (O) (ONa) ₂ , P (O) (OK) ₂ , C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O ) N (—C _1-6 alkyl) ₂ , C (O) -pyridyl, or C (O) —C _1-6 alkylene-NH ₂ ;
R ³ is H, C _1-4 alkyl, C _1-4 fluoroalkyl, or CH ₂ -C _3-5 cycloalkyl;
R ⁴ is H, C _1-4 alkyl, C _1-4 fluoroalkyl, or CH ₂ -C _3-5 cycloalkyl;
R ⁵ is, _{H, C 1-4 alkyl, C 1-4} fluoroalkyl, _{C 1-4} alkyl substituted with _{OH, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5} cycloalkyl or CH, _2- C _3-5 cycloalkyl;
R ^5A is H or C _1-4 alkyl;
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-5 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) When either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H; and (C) When R ³ and R ⁴ are not H, R ⁵ and R ^5A are both H;
R ⁶ is:

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
R ^6A is H or C _1-4 alkyl;
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached form a C _3-5 cycloalkyl optionally substituted with phenyl, where the phenyl is optionally substituted with 1 to 2 X ^B ;
Each X ^B and each X ^C is
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl,
(18) CH ₂ OH, and (19) CH ₂ O—C _1-3 alkyl,
Independently selected from the group consisting of
m is an integer equal to 0, 1, or 2;
n is an integer equal to 0, 1, or 2;
Each of ^{X A} is, independently:
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl, or (18)
(A) cyclopropyl,
(B) CF ₃ ,
(C) OH,
(D) O—C _1-3 alkyl,
(E) OCF ₃ ,
(F) Cl,
(G) Br,
(H) F,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) -C _1-3 alkyl,
(M) N (—C _1-3 alkyl) ₂ ,
(N) C (O) —C _1-3 alkyl,
(O) CO ₂ H, or (p) C (O) O—C _1-3 alkyl,
C _1-3 alkyl substituted with
k is an integer equal to 0, 1, or 2;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbon atoms to which they are attached. Together with a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains heteroatoms,
R ⁷ is H, C _1-6 alkyl, C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N (—C _1-6 alkyl) ₂ , C _(O) -HetA, a C (O) OCH 2 -HetA, C (O) -HetB , or _{C (O) OCH 2 -HetB,} ,
R ⁸ is H or C _1-4 alkyl;
HetA is a heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, and quinoxalinyl, wherein each heteroaryl is independently CH ₃ , CF ₃ , OH, OCH ₁ , OCF ₃ , Cl, Br, F, CN, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , C (O) CH ₃ , CO ₂ CH ₃ , or SO ₂ CH ₃ And HetB is optionally oxidized to tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl (S is optionally oxidized to S (O) or S (O) _2. A saturated heterocyclic ring selected from the group consisting of: and each ring is independently C _{3, CH} 2 CH _{3, oxo, C (O) N (CH} 3) 2, C (O) CH 3, CO 2 CH 3 , or 1 or 2 substituents is S _(O) 2 CH _3, Optionally substituted with
2. A compound according to claim 1 or a salt acceptable as a pharmaceutical product.
This corresponds to the original PV claim 2. 4. A compound according to claim 3 which is a compound of formula IA.

Or a pharmaceutically acceptable salt thereof (wherein
R ¹ is C _1-6 alkyl;
R ³ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ⁴ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ⁵ is H, CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
However:
(A) When R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , and R ⁵ is CH ₃ , CF ₃ , CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl. And (B) at least one of R ³ , R ⁴ , and R ⁵ is H;
R ⁶ is:

Where the asterisk (*) indicates the point of attachment to the other part of the compound,
Each of ^{X A} is, independently:
(1) C _1-3 alkyl,
(2) cyclopropyl,
(3) CF ₃ ,
(4) OH,
(5) O—C _1-3 alkyl,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NO ₂ ,
(12) NH ₂ ,
(13) N (H) -C _1-3 alkyl,
(14) N (—C _1-3 alkyl) ₂ ,
(15) C (O) —C _1-3 alkyl,
(16) CO ₂ H,
(17) C (O) O—C _1-3 alkyl, or (18)
(A) cyclopropyl,
(B) CF ₃ ,
(C) OH,
(D) O—C _1-3 alkyl,
(E) OCF ₃ ,
(F) Cl,
(G) Br,
(H) F,
(I) CN,
(J) NO ₂ ,
(K) NH ₂ ,
(L) N (H) -C _1-3 alkyl,
(M) N (—C _1-3 alkyl) ₂ ,
(N) C (O) —C _1-3 alkyl,
(O) CO ₂ H, or (p) C (O) O—C _1-3 alkyl,
C _1-3 alkyl substituted with
k is an integer equal to 0, 1, or 2, and R ⁷ is H, C (O) —C _1-6 alkyl, C (O) O—C _1-6 alkyl, C (O) N ( -C is a _{1-6 alkyl)} 2, C _(O) -HetA, or C (O) -HetB,. ). R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ F, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ² is CH ₂ OH, CH (CH ₃ ) OH, CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH ₂ OR ^P , or CH (CH ₃ ) —OR ^P where R ^P is , P (O) (OH) ₂ , P (O) (ONa) ₂ , or C (O) CH ₃ ,
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl , cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH ₂ - cyclobutyl,
R ^5A is H or CH ₃
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form a C _3-5 cycloalkyl,
However:
(A) when R ² is CH ₂ OH or CH ₂ OR ^P , at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H;
(B) When either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H; and (C) When R ³ and R ⁴ are not H, R ⁵ and R ^5A are both H;
R ⁶ is:

And
R ^6A is H;
Alternatively, R ⁶ and R ^6A together with the carbon to which they are attached form a cyclopropyl substituted with phenyl, where the phenyl is optionally substituted with 1 to 2 X ^B
Each X ^B and each X ^C is
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
Independently selected from the group consisting of
Each of ^{X A} is, independently:
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH,
(17) CH ₂ OCH ₃ ,
₍₁₈₎ CH 2 _NH 2,
_{(19) CH 2 N (H} ) CH 3,
_{(20) CH 2 N (CH} 3) 2,
(21) CH (CH ₃ ) OH,
(22) CH (CH ₃ ) OCH ₃ ,
(23) CH (CH ₃ ) NH ₂ ,
(24) CH (CH ₃ ) N (H) CH ₃ , or (25) CH (CH ₃ ) N (CH ₃ ) ₂ ,
And
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbon atoms to which they are attached. Together with a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle is independently selected from N, O and S Contains heteroatoms,
R ⁷ is H, CH ₃ , C (O) CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , C (O) N (CH ₃ ) ₂ , C (O) — morpholinyl, C (O) - pyridyl or _{C (O) O-CH 2} , - pyridyl, and the salts that can be accepted as a compound or pharmaceutical of claim 3 ^{R 8} is H or CH _3. R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ cyclopropyl, - CH ₂ F, cyclobutyl or CH _2,
R ² is CH ₂ OH, CH (CH ₃ ) OH, or CH ₂ NH ₂ ;
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is H, CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl Or cyclopropyl,
R ^5A is H or CH ₃ except that when R ^5A is CH ₃ , R ⁵ is CH ₃ ;
Alternatively, R ⁵ and R ^5A together with the carbon atom to which both are attached form cyclobutyl or cyclopentyl,
However:
(A) When R ² is CH ₂ OH, at least one of R ³ , R ⁴ , R ⁵ and R ^5A is not H,
(B) When either or both of R ⁵ and R ^5A are not H, at least one of R ³ and R ⁴ is H; and (C) When R ³ and R ⁴ are not H, R ⁵ and R ^5A are both H;
R ⁶ is:

And
R ^6A is H;
Alternatively, R ⁶ and R ^6A form a cyclopropyl substituted with phenyl with the carbon to which they are attached,
There are one or two X ^A groups in the phenylsulfonyl moiety, where one X ^A is in the para position of the phenyl ring and CH ₃ , Cl, Br, F, NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH, and the other optional X ^A is in the meta position of the phenyl ring and is Cl, Br, or F;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms, it forms a thiazole fused to the phenyl ring.

May be provided,
R ⁷ is H, CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , or C (O) O—CH ₂ -pyridyl, and R ⁸ is H or CH ₃ . 6. A compound according to claim 5 or a salt acceptable as a pharmaceutical product. R ² is CH ₂ OH,
R ³ is H;
R ⁴ is H;
However, either or both of R ⁵ and R ^5A are not H,
R ^6A is H;
R ⁷ is a salt that can be accepted as C (O) compound of OCH ₃ a is and ^{R 8} are according to any one of claims 1, 3, 5 and 6 is H or pharmaceutical. 2. A compound according to claim 1 which is a compound of formula II.

Or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 which is a compound of formula III.

Or a pharmaceutically acceptable salt thereof (wherein
R ⁵ is _{C 1-6 alkyl, C 1-6} fluoroalkyl, _{C 1-6} alkyl substituted with _{OH, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6} cycloalkyl or _{C, 3-} C _1-6 alkyl substituted with ₆ cycloalkyl. ). R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₂ F, cyclopropyl, cyclobutyl, CH ₂ -cyclopropyl, or CH ₂ -cyclobutyl,
R ² is CH ₂ OH, CH (CH ₃ ) OH, CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH ₂ OR ^P , or CH (CH ₃ ) —OR ^P where R ^P is , P (O) (OH) ₂ , P (O) (ONa) ₂ , or C (O) CH ₃ ,
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, cyclo cyclopropyl, cyclobutyl, CH ₂ - cyclopropyl, or CH _2, - cyclobutyl,
Provided that at least one of R ³ and R ⁴ is H;
R ⁶ is:

And
Each X ^B and each X ^C is
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
Independently selected from the group consisting of
m is 0, 1 or 2;
n is 0, 1, or 2;
Each of ^{X A} is, independently:
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH,
(17) CH ₂ OCH ₃ ,
₍₁₈₎ CH 2 _NH 2,
_{(19) CH 2 N (H} ) CH 3,
_{(20) CH 2 N (CH} 3) 2,
(21) CH (CH ₃ ) OH,
(22) CH (CH ₃ ) OCH ₃ ,
(23) CH (CH ₃ ) NH ₂ ,
(24) CH (CH ₃ ) N (H) CH ₃ , or (25) CH (CH ₃ ) N (CH ₃ ) ₂ ,
And
k is 0, 1, or 2;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbon atoms to which they are attached. Together with a 5- or 6-membered saturated or unsaturated heterocycle fused to the phenyl ring, wherein the heterocycle includes 1 to 2 heterocycles independently selected from N, O and S Contains atoms,
R ⁷ is H, CH ₃ , C (O) CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , C (O) N (CH ₃ ) ₂ , C (O) — morpholinyl, C (O) - pyridyl or _{C (O) O-CH 2} , - pyridyl, and the salts that can be accepted as a compound or pharmaceutical of claim 9 ^{R 8} is H or CH _3. R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ cyclopropyl, - CH ₂ F, cyclobutyl or CH _2,
R ² is CH ₂ OH, CH (CH ₃ ) OH, or CH ₂ NH ₂ ;
R ³ is H or CH ₃
R ⁴ is H or CH ₃
R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, or Cyclopropyl,
Provided that at least one of R ³ and R ⁴ is H;
R ⁶ is:

And
There are one or two X ^A groups in the phenylsulfonyl moiety, where one X ^A is in the para position of the phenyl ring and CH ₃ , Cl, Br, F, NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH, and the other optional X ^A is in the meta position of the phenyl ring and is Cl, Br, or F;
Alternatively, when two X ^A substituents are present on the phenyl ring and two X ^A are attached to adjacent carbon atoms of the phenyl ring, the two X ^A are the carbons to which they are attached. Together with the atoms, it forms a thiazole fused to the phenyl ring.

May be provided,
R ⁷ is H, CH ₃ , C (O) OCH ₃ , C (O) OC (CH ₃ ) ₃ , or C (O) O—CH ₂ -pyridyl, and R ⁸ is H or CH ₃ . 11. A compound according to claim 10, or a salt acceptable as a pharmaceutical product. R ² is CH ₂ OH,
R ³ is H;
R ⁴ is H;
R ⁷ is a salt that can be accepted as C (O) A compound according to any one of OCH ₃ a is and ^{R 8} from claim 9 a H 11 or a pharmaceutical. 10. A compound according to claim 9, which is a compound of formula IV.

Or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 13 which is a compound of formula V.

Or a pharmaceutically acceptable salt thereof (wherein
R ¹ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH (CH ₃ ) ₂ , CH ₂ CH ₂ cyclopropyl, - CH ₂ F, cyclobutyl or CH _2,
R ⁵ is CH ₃ , CH ₂ CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH ₂ CH ₃ , C (CH ₃ ) ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ OH, ethenyl, ethynyl, or Cyclopropyl,
X ^A is NH ₂ , C (O) CH ₃ , CH ₂ OH, or CH (CH ₃ ) OH;
Each X ^B and each X ^C is
(1) CH ₃ ,
(2) CH ₂ CH ₃ ,
(3) CF ₃ ,
(4) OH,
(5) OCH ₃ ,
(6) OCF ₃ ,
(7) Cl,
(8) Br,
(9) F,
(10) CN,
(11) NH ₂ ,
(12) N (H) CH ₃ ,
(13) N (CH ₃ ) ₂ ,
(14) C (O) CH ₃ ,
(15) C (O) OCH ₃ ,
(16) CH ₂ OH, and (17) CH ₂ OCH ₃ ,
Independently selected from the group consisting of
m is an integer equal to 0, 1, or 2;
n is an integer equal to 0, 1, or 2. ). R ¹ _{is, CH (CH 3) 2,} CH 2 CH (CH 3) 2 or a salt thereof acceptable compound according or as a medicament to claim _{14 CH 2 CH 2 CH (CH} 3) a _2,. m and n are both either 0 or both 1, and X ^B and X ^C is (i) both F and both para substituent, (ii) both F and both meta-substituent Or (iii) a compound according to any of claims 14 or 15, or a pharmaceutically acceptable salt thereof, both of which are Cl and both are para substituents. (2S) -2-amino-N- {5-[[(4-aminophenyl) sulfonyl]-(3-methylbutyl) amino] -6-hydroxyheptyl} -3,3-diphenylpropanamide,
Methyl [(1S) -2-({6-amino-5-[[(4-aminophenyl) -sulfonyl]-(3-methylbutyl) amino] -hexyl) -amino) -1- (diphenylmethyl) -2 -Oxoethyl] carbamate,
(2S) -2-amino-N-((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] -amino} hexyl) -3,3- Diphenylpropanamide,
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-3-methyl-5-{(3-methylbutyl) [(4-methylphenyl) -sulfonyl] amino} hexyl Amino] -2-oxoethyl} carbamate,
Methyl {(1S) -1- (diphenylmethyl) -2-[((5S) -6-hydroxy-2-methyl-5-{(3-methylbutyl) [(4-methylphenyl) sulfonyl] amino} hexylamino ] -2-oxoethyl} carbamate,
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-methylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (diphenylmethyl) -2-oxoethyl] carbamate,
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3R) -3-methylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (diphenylmethyl) -2-oxoethyl] carbamate,
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-ethylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (diphenylmethyl) -2-oxoethyl] carbamate,
N-{(1S, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -Na- (methoxycarbonyl)- b-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -6-amino-5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl)- L-phenylalaninamide,
N-{(1S, 5S) -5-[(1,3-benzothiazol-6-ylsulfonyl) (3-methylbutyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-propylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl)- L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -6-hydroxy-1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl) -L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-isopropylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-fluoropropyl) amino] -6-hydroxy-1-propylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -6-hydroxy-1-isopropylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-fluoropropyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1-isopropylhexyl} -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-amino-3-bromophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
Methyl [(1S) -2-({(5S) -5-[[3-fluoro-4-aminophenyl) sulfonyl]-((3S) -3-cyclopropylbutyl) amino] -6-hydroxy-1- Methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate,
N-{(1R, 5S) -1-cyclopropyl-5-[{[3-fluoro-4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -6-hydroxyhexyl} -4-fluoro -Β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-amino-3-fluorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-chlorophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-acetylphenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -4-fluoro-β- (4-fluoro Phenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -5-[(1,3-benzothiazol-6-ylsulfonyl) (isobutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -4-fluoro-β- (4-fluoro Phenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -5-[(1,3-benzothiazol-6-ylsulfonyl) (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -2-chloro-Nα- (Methoxycarbonyl) -L-phenylalaninamide,
Methyl [(1S) -2-({(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} amino) -1 -(1-naphthylmethyl) -2-oxoethyl] carbamate,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -2-bromo-Nα- (methoxycarbonyl)- L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-fluoropropyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
Methyl [2-({(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} amino) -1- (5H-dibenzo [A, d] [7] annulen-5-yl) -2-oxoethyl] carbamate,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -1-ethyl-6-hydroxyhexyl} -2-bromo-Nα- (methoxycarbonyl) -L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -1-ethyl-6-hydroxyhexyl} -2-chloro-Nα- (methoxycarbonyl) -L- Phenylalaninamide,
tert-butyl {(1R, 2R) -1-[({(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} Amino) carbonyl] -2-phenylcyclopropyl} carbamate,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -β-phenyl-Nα-[(pyridine-4 -Ylmethoxy) carbonyl] -L-phenylalaninamide,
Methyl [2-({(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} amino) -2-oxo-1- (9H-xanthen-9-yl) ethyl] carbamate,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -Nα-methyl-β- Phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -1-ethyl-6-hydroxyhexyl} -β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-isopropylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -3-fluoro-β- (3-fluorophenyl)- Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -2,3-dichloro-Nα- (methoxycarbonyl)- L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1-methylhexyl} -3-fluoro-β- (3-fluorophenyl)- Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-[(1S, 5S) -5- (ethyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
2-Chloro-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -5-[(1,3-benzothiazol-6-ylsulfonyl) (3-methylbutyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (methyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (ethyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (methyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (cyclopropylmethyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
2-Chloro-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (methyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
2-chloro-N-[(1S, 5S) -5- (ethyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl) -L -Phenylalaninamide,
2-Chloro-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -2-chloro-Nα- (methoxycarbonyl) -L- Phenylalaninamide,
2-Bromo-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
2-Bromo-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-[(1S, 5S) -5-((3-fluoropropyl) {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -2-bromo-Nα- (methoxycarbonyl) -L- Phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-[(1S, 5S) -5- (cyclobutyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxy-1-methylhexyl] -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (ethyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (methyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -Nα-methyl-β-phenyl-L-phenylalaninamide,
2-chloro-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl}-(isobutyl) amino] hexyl} -Nα- (methoxy Carbonyl) -L-phenylalaninamide,
2-Chloro-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -Nα- (methoxycarbonyl ) -L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] hexyl} -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -1-cyclopropyl-5- (ethyl {[4- (hydroxymethyl) phenyl] sulfonyl} amino) -6-hydroxyhexyl] -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (methyl) amino] hexyl} -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (methyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (ethyl) amino] -1-cyclopropyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3-methylbutyl) amino] hexyl} -4 -Fluoro-β- (4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -1-tert-butyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
N-[(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl)- β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-isopropylhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-vinylhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-vinylhexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1- (pentafluoroethyl) hexyl] -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide,
N-{(1R, 5S) -1-ethynyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
2-Chloro-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- ( Methoxycarbonyl) -L-phenylalaninamide,
2-Chloro-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3-methylbutyl) amino] Hexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -4-fluoro-β- ( 4-fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -4-fluoro-β- ( 4-fluorophenyl) -L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (3-methylbutyl) amino] hexyl} -4 -Fluoro-β- (4-fluorophenyl) -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -4-fluoro-β- (4-fluoro Phenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
2-Chloro-N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
2-Chloro-N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -4-fluoro-β- (4- Fluorophenyl) -Nα- (methoxycarbonyl) -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα-methyl-β-phenyl-L- Phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -Nα-methyl-β-phenyl-L -Phenylalaninamide,
2-chloro-N-{(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-isopropylhexyl} -Nα- (methoxy Carbonyl) -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα-methyl-β-phenyl- L-phenylalaninamide,
N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα-methyl-β-phenyl -L-phenylalaninamide,
N-{(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] -1-isopropylhexyl} -Nα-methyl-β-phenyl- L-phenylalaninamide,
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -β-phenyl-L-phenylalaninamide ,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isobutyl) amino] hexyl} -β-phenyl-L-phenylalaninamide;
N-{(5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] hexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -Nα-methyl-β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -β-phenyl-L-phenylalaninamide;
2-Bromo-N-{(1R, 5S) -1-cyclopropyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] hexyl} -Nα- (methoxycarbonyl ) -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] hexyl} -Nα-methyl-β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] hexyl} -β-phenyl-L-phenylalaninamide;
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
Methyl [(1S) -2-({(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] hexyl} amino) -1 -(1-naphthylmethyl) -2-oxoethyl] carbamate,
N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -Β-phenyl-L-phenylalaninamide,
2-Chloro-N-[(1R, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (propyl) amino] -1- (trifluoromethyl) hexyl] -Nα- (Methoxycarbonyl) -L-phenylalaninamide,
4-chloro-β- (4-chlorophenyl) -N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino Hexyl} -Nα- (methoxycarbonyl) -L-phenylalaninamide,
2,3-dichloro-N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxy Carbonyl) phenylalaninamide,
3-Fluoro-β- (3-fluorophenyl) -N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methyl Hexyl} -Nα- (methoxycarbonyl) phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) -amino] hexyl} -Nα- ( Methoxycarbonyl) -β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-acetylphenyl) sulfonyl] (isopropyl) amino] -1-ethyl-6-hydroxyhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) amino] -1-methylhexyl} -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide,
N-{(1S, 5S) -5-[[(4-acetylphenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N- (1-{(4S) -4-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -5-hydroxypentyl} cyclopentyl) -Nα- (methoxycarbonyl) -β-phenyl-L -Phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -β-phenyl-L-phenylalaninamide,
N- (1- {4-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -5-hydroxypentyl} cyclobutyl) -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (methoxycarbonyl) -β-phenyl- L-phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isobutyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (3-fluoropropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -Nα-methyl-β-phenyl-L-phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -2-chloro-L-phenylalaninamide,
N- [5-[[(4-Aminophenyl) sulfonyl] (3-methylbutyl) amino] -6-hydroxy-1- (hydroxymethyl) hexyl] -Nα- (methoxycarbonyl) -β-phenyl-L-phenylalanine Amide,
And a pharmaceutically acceptable salt thereof selected from the group consisting of: N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
Methyl [(1S) -2-({(5S) -5-[[4-aminophenyl) sulfonyl]-((3S) -3-ethylbutyl) amino] -6-hydroxy-1-methylhexyl) amino)- 1- (diphenylmethyl) -2-oxoethyl] carbamate,
N-{(1S, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl-L- Phenylalaninamide,
N-{(5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1,1-dimethylhexyl} -β-phenyl-L-phenylalaninamide,
Methyl [(1S) -2-({(5S) -5-[[3-fluoro-4-aminophenyl) sulfonyl]-((3S) -3-cyclopropylbutyl) amino] -6-hydroxy-1- Methylhexyl) amino) -1- (diphenylmethyl) -2-oxoethyl] carbamate,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (propyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-[(1R, 5S) -5-[[(4-aminophenyl) sulfonyl] (isopropyl) amino] -6-hydroxy-1- (trifluoromethyl) hexyl] -Nα- (methoxycarbonyl) -β- Phenyl-L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα- (methoxycarbonyl) -β -Phenyl-L-phenylalaninamide,
N-{(1S, 5S) -1-ethyl-6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (3-methylbutyl) amino] hexyl} -Nα-methyl-β-phenyl- L-phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[{[4- (hydroxymethyl) phenyl] sulfonyl} (isopropyl) amino] -1-methylhexyl} -Nα- (methoxycarbonyl) -β-phenyl -L-phenylalaninamide,
N-{(1S, 5S) -6-hydroxy-5-[({4-[(1S) -1-hydroxyethyl] phenyl} sulfonyl) (isopropyl) amino] -1-methylhexyl} -Nα- (methoxy Carbonyl) -β-phenyl-L-phenylalaninamide,
18. A compound according to claim 17 and their pharmaceutically acceptable salts selected from the group consisting of:   A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   A method for treating or preventing HIV infection, or treating or preventing HIV infection in a subject in need of treating, preventing or delaying the onset of AIDS, or treating, preventing or delaying the onset of AIDS. A method comprising administering to a subject an effective amount of a compound according to any of claims 1 to 18 or a pharmaceutically acceptable salt thereof.   Inhibition of HIV protease, treatment or prevention of HIV infection, or treatment, prevention of AIDS, or inhibition of HIV protease, treatment or prevention of HIV infection, or treatment, prevention, or AIDS in a subject in need thereof 19. A compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in preparing a medicament for delaying its onset.